Effects Of Hormone Therapy Research Articles

PFKFB3 regulates breast cancer tumorigenesis and Fulvestrant sensitivity by affecting ERα stability

Estrogen receptor alpha (ERα) is expressed in approximately 70% of breast cancer cases and determines the sensitivity and effectiveness of endocrine therapy. 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase3 (PFKFB3) is a glycolytic enzyme that is highly expressed in a great many human tumors, and recent studies have shown that it plays a significant role in improving drug sensitivity. However, the role of PFKFB3 in regulating ERα expression and the underlying mechanism remains unclear. Here, we find by using immunohistochemistry (IHC) that PFKFB3 is elevated in ER-positive breast cancer and high expression of PFKFB3 resulted in a worse prognosis. In vitro and in vivo experiments verify that PFKFB3 promotes ER-positive breast cancer cell proliferation. The overexpression of PFKFB3 promotes the estrogen-independent ER-positive breast cancer growth. In an estrogen-free condition, RNA-sequencing data from MCF7 cells treated with siPFKFB3 showed enrichment of the estrogen signaling pathway, and a luciferase assay demonstrated that knockdown of PFKFB3 inhibited the ERα transcriptional activity. Mechanistically, down-regulation of PFKFB3 promotes STUB1 binding to ERα, which accelerates ERα degradation by K48-based ubiquitin linkage. Finally, growth of ER-positive breast cancer cells in vivo was more potently inhibited by fulvestrant combined with the PFKFB3 inhibitor PFK158 than for each drug alone. In conclusion, these data suggest that PFKFB3 is identified as an adverse prognosis factor for ER-positive breast cancer and plays a previously unrecognized role in the regulation of ERα stability and activity. Our results further explores an effective approach to improve fulvestrant sensitivity through the early combination with a PFKFB3 inhibitor.

Navigating the Intricacies of Tumor Heterogeneity: An Insight into Potential Prognostic Breast Cancer Biomarkers.

Breast cancer is a heterogeneous disease with diverse histological and molecular subtypes. Luminal breast tumors are the most diagnosed subtype. In luminal breast cancer, hormone receptors (including ER, PR, HER2) play a diagnostic and prognostic role. Despite the effectiveness of endocrine therapy in luminal breast tumors, tumor recurrence and resistance occur, and this may highlight evolutionary strategies for survival driven by stemness. In this review we thus consider the association between estrogen signaling and stemness in mediating tumor processes. Many studies report stemness as one of the factors promoting tumor progression. Its association with estrogen signaling warrants further investigation and provides an opportunity for the identification of novel biomarkers which may be used for diagnostic, prognostic, and therapeutic purposes. Breast cancer stem cells have been characterized (CD44+ CD24-) and their role in promoting treatment resistance and tumor recurrence widely studied; however, the complexity of tumor progression which also involve microenvironmental factors suggests the existence of more varied cell phenotypes which mediate stemness and its role in tumor progression.

High SLC20A1 Expression Indicates Poor Prognosis in Prostate Cancer.

High expression of solute carrier family 20 member 1 (SLC20A1) indicates poor clinical outcomes for patients with breast cancer subtypes treated with endocrine therapy and radiotherapy. However, the association between SLC20A1 expression and clinical outcomes in prostate cancer remains to be determined. Open-source datasets (The Cancer Genome Atlas prostate, Stand Up to Cancer-Prostate Cancer Foundation Dream Team, and The Cancer Genome Atlas PanCancer Atlas) were downloaded and analyzed. SLC20A1 expression was analyzed in prostate cancer and normal prostate tissue. Survival analysis using Kaplan-Meier curves and Cox regression analysis were performed to examine patient prognosis, as well as the effects of endocrine therapy and radiotherapy on high SLC20A1 expression in patients with prostate cancer. SLC20A1 was higher in prostate cancer than in normal prostate tissues. High SLC20A1 expression predicted poor disease-free and progression-free survival. Following endocrine therapy, no significant difference in prognosis was observed between patients with high SLC20A1 and those with low SLC20A1 expression. However, following radiotherapy, high SLC20A1 expression tended to be associated with a poor clinical outcome. SLC20A1 may serve as a prognostic biomarker for prostate cancer, and the recommended treatment for patients with high SLC20A1 expression is endocrine therapy.

Abstract 3717: Defining the mechanism of ER receptor transcription complex activity and its effect on epigenetic modulations using super resolution microscopy

Abstract Estrogen Receptor α (ERα) is expressed in ER+ breast cancers, one of the leading causes of death among women. Despite effectiveness of endocrine therapy, a significant number of patients experience resistance to these treatments. One of the major hurdles is lack of comprehensive information about ERα transcriptional complex activity. While biochemical assays have improved our knowledge significantly, it is critical to imply techniques that allow direct visualization of ERα activity and gain spatiotemporal information. We used super resolution microscopy to examine the mechanism of ERα transcriptional activity. We showed that ERα interactions with its co-activators (P300, SRC-3), is influenced upon administration of Tamoxifen and Fulvestrant, an effect that is lost in cells carrying multination in ERα ligand binding site. Additionally mutant cells are no longer able to recruit ERα co-inhibitor (NCORI). Using STORM microscopy, we showed estrogen treatment caused an “open” chromatin (H3K27ac) structure which may represent active areas of gene expression, while Tamoxifen and Fulvestrant treatments caused chromatin to form “closed” structures which likely represent close and inactive phase of chromatin. Citation Format: Tara Akhshi, Myles Brown. Defining the mechanism of ER receptor transcription complex activity and its effect on epigenetic modulations using super resolution microscopy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3717.

Long-term Survival in Breast Cancer Patients Is Associated with Contralateral Parenchymal Enhancement at MRI: Outcomes of the SELECT Study.

Background Several single-center studies found that high contralateral parenchymal enhancement (CPE) at breast MRI was associated with improved long-term survival in patients with estrogen receptor (ER)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Due to varying sample sizes, population characteristics, and follow-up times, consensus of the association is currently lacking. Purpose To confirm whether CPE is associated with long-term survival in a large multicenter retrospective cohort, and to investigate if CPE is associated with endocrine therapy effectiveness. Materials and Methods This multicenter observational cohort included women with unilateral ER-positive HER2-negative breast cancer (tumor size ≤50 mm and ≤three positive lymph nodes) who underwent MRI from January 2005 to December 2010. Overall survival (OS), recurrence-free survival (RFS), and distant RFS (DRFS) were assessed. Kaplan-Meier analysis was performed to investigate differences in absolute risk after 10 years, stratified according to CPE tertile. Multivariable Cox proportional hazards regression analysis was performed to investigate whether CPE was associated with prognosis and endocrine therapy effectiveness. Results Overall, 1432 women (median age, 54 years [IQR, 47-63 years]) were included from 10 centers. Differences in absolute OS after 10 years were stratified according to CPE tertile as follows: 88.5% (95% CI: 88.1, 89.1) in tertile 1, 85.8% (95% CI: 85.2, 86.3) in tertile 2, and 85.9% (95% CI: 85.4, 86.4) in tertile 3. CPE was independently associated with OS, with a hazard ratio (HR) of 1.17 (95% CI: 1.0, 1.36; P = .047), but was not associated with RFS (HR, 1.11; P = .16) or DRFS (HR, 1.11; P = .19). The effect of endocrine therapy on survival could not be accurately assessed; therefore, the association between endocrine therapy efficacy and CPE could not reliably be estimated. Conclusion High contralateral parenchymal enhancement was associated with a marginally decreased overall survival in patients with estrogen receptor-positive and human epidermal growth factor receptor 2-negative breast cancer, but was not associated with recurrence-free survival (RFS) or distant RFS. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Honda and Iima in this issue.

Comparison of changes in lipid profiles of premenopausal women with early-stage breast cancer treated with different endocrine therapies

Adjuvant endocrine therapy improves the prognosis of early breast cancer with hormone receptor positivity. However, there is no systematic report on the effect of endocrine therapy (particularly ovarian function suppression, OFS) on serum lipids in premenopausal women. This retrospective cohort study aimed to determine whether various endocrine treatments had different effects on blood lipids. This study enrolled 160 premenopausal patients with stage I–III breast cancer in eastern China. The initial diagnostic information was retrieved from patient's medical records, including age at the time of diagnosis, tumor characteristics, anticancer treatment and past medical history. The changes in blood lipids in patients receiving different types of endocrine therapy were compared at the 3rd, 6th, 12th, and 24th months after initiating endocrine therapy. Generalized linear mixed model was used in our analyses. Our data revealed that low-density lipoprotein cholesterol (LDL-C) levels in patients with tamoxifen (TAM) were significantly lower in the 6th, 12th, and 24th months than that in the 3rd month, while high-density lipoprotein cholesterol (HDL-C) levels in the 6th, 12th, and 24th months were significantly higher than that in the 3rd month, indicating that blood lipid levels generally improved with time. While in TAM plus OFS group, HDL-C levels were significantly higher in the 24th month than in the 3rd month, total cholesterol (TC) levels were significantly higher in the 24th month than in the 6th month. The lipid profiles of OFS plus aromatase inhibitor (AI) group did not show significant differences at any time point but were significantly higher than those of the other two groups especially in LDL and TC. TAM group tended to have lower serum lipid levels. With longer follow-up, no statistically significant difference in values was observed between TAM and TAM plus OFS groups at various time points. Compared with the other two groups, OFS plus AI group presented an increasing trend toward LDL-C and TC. The risk of dyslipidemia requires further investigation using a large sample size.

Effects of Endocrine Therapy on Cardiovascular Diseases and Type 2 Diabetes Among Breast Cancer Survivors: The National Health Insurance Service Database of Korea.

Background Although endocrine therapy is an effective treatment for breast cancer, its antiestrogen effects are associated with increased risks of cardiovascular diseases and type 2 diabetes. This study aimed to investigate the association between endocrine therapy and the risk of cardiovascular diseases and type 2 diabetes among breast cancer survivors in Korea, in consideration of various age groups. Methods and Results In the National Health Insurance Service database of Korea, a total of 133 171 patients with breast cancer aged ≥20 years were included in the current study. Endocrine therapy was treated as time-varying exposure, and patients were categorized as nonusers, selective estrogen receptor modulator users, aromatase inhibitor users, and both users. Time-dependent Cox regression models were used to estimate hazard ratios (HRs) and 95% CIs. Age at diagnosis, socioeconomic status, histological type, other treatments, and comorbidities were adjusted in the model. Compared with nonusers, selective estrogen receptor modulator users were associated with higher risks of stroke (HR, 1.20 [95% CI, 1.04-1.40]) and venous thromboembolism (HR, 1.47 [95% CI, 1.13-1.90]), whereas aromatase inhibitor users were associated with a higher risk of coronary heart disease (HR, 1.22 [95% CI, 1.06-1.41]). The risk of type 2 diabetes was associated with selective estrogen receptor modulator users (HR, 1.13 [95% CI, 1.05-1.21]), aromatase inhibitor users (HR, 1.14 [95% CI, 1.05-1.23]), and both users (HR, 1.24 [95% CI, 1.10-1.39]). In particular, the risk of a composite of cardiovascular diseases was higher in younger or premenopausal patients. Conclusions In breast cancer survivors in Korea, endocrine therapy is associated with a higher risk of cardiovascular diseases and type 2 diabetes. Monitoring of cancer comorbidities after endocrine therapy is needed in younger and older patients.

Tumor copy number alterations were associated with primary endocrine resistance in ER+ breast cancer.

e12567 Background: Several studies has showed alterations in genes were associated with endocrine resistance in breast cancer. Nevertheless, genomic landscape in primary endocrine-resistant breast cancer has not been thoroughly reported. Whether the genomic landscape of primary endocrine-resistant breast cancer is different from that of secondary endocrine-resistant breast cancer is unknown. Methods: We analyzed the genomic landscape of primary tumor of consecutive patients with estrogen-receptor positive (ER+) breast cancer in real-world clinical practice in our center between September, 2019 to December, 2020. According to the duration of endocrine treatment, we classified them into primary endocrine resistance group and secondary endocrine resistance group. Results: A total of 41 tumor samples of which 25 cases in primary endocrine resistance and 16 cases in secondary endocrine resistance were included for analysis. TP53 (65.9%, 27/41), PIK3CA (46.3%, 19/41), MYC (36.6%, 15/41), MCL1 (31.7%, 13/41), CCND1 (31.7%, 13/41) were the most frequently altered genes in all 41 BCs. Copy number amplification of MYC was common in primary endocrine resistant group (48.0%, 12/25), while lower in secondary endocrine resistant group (18.8%, 3/16, P = NS). Copy number alteration (CNA) of CCND1, MCL1, FGF19, ZNF217, ZNF703 and FGFR1 were commonly observed in primary endocrine resistance group. Percentage of CNA in all mutation types was significant increased in primary endocrine resistance group than in secondary resistance group (33.0% vs. 21.0%, P = 0.03). Then we further analyzed and found CNA burden, which was defined as number rather the percentage of the CNA event, was associated with the prognosis in ER+ breast cancer. When defining 6 as the cut-off value of CNA-High, DFS, PFS and OS were practically poorer in patients with CNA-High than those with CNA-Low. Conclusions: Copy number alterations were more commonly seen in primary endocrine-resistant breast cancer and associated with prognosis in ER+ breast cancer. This founding urged to further investigate the prognostic value of CNA burden in predicting the effectiveness of endocrine therapy.

Acupuncture for hot flashes in hormone receptor-positive breast cancer, a pooled analysis of individual patient data from parallel randomized trials.

12124 Background: Hot flashes are a common side effect of endocrine therapy in breast cancer patients (pts). In a coordinated multinational study, we evaluated the impact of acupuncture on hot flashes and related symptoms in hormone receptor-positive breast cancer pts undergoing adjuvant endocrine therapy in the USA, China, and South Korea. Methods: Parallel randomized trials were conducted at three sites: Dana-Farber Cancer Institute, USA; Jiangsu Hospital of Traditional Chinese Medicine, China; and Daegu Catholic University Medical Center, Republic of Korea, using the same inclusion/exclusion criteria, randomization, and measures. Breast cancer pts receiving adjuvant endocrine therapy and having ≥14 hot flashes per week were randomized equally to acupuncture (A) or usual care (UC); randomization was stratified by number of hot flashes per day (2-6 or 7+). Pts in arm A received a standardized acupuncture protocol twice per week for 10 weeks; pts in the UC arm received usual care. Symptoms were assessed at baseline and week 10. The primary endpoint was change in the Endocrine Symptom Subscale (ESS) of the Functional Assessment of Cancer Therapy-Endocrine Systems (FACT-ES). Secondary endpoints included changes in the FACT-Breast (FACT-B) and Daily Hot Flash Score (DHFS), a measure incorporating hot flash frequency and severity. Target enrollment was 160 pts (USA 80, China 40, Korea 40) providing 84% power to detect a clinically meaningful change in the ESS. Analyses were intention-to-treat. A pooled analysis of individual patient data was performed using linear models adjusted for site and baseline number of hot flashes. Results: Between Jan. 2019 and June 2021, 158 female pts with stage 0-III breast cancer were randomized from the USA (n=78), China (n=40), and South Korea (n=40). Median age was 48 years (range: 25 to 73). At baseline, pts reported similar numbers of hot flashes between study arms (6.2± 4.3 vs. 6.5± 3.8 per day). At week 10, pts in arm A reported statistically significant improvements in ESS score, FACT-B total score and DHFS compared with the UC arm (Table). The reduction in the DHFS from baseline in arm A was 53%. There were no serious adverse events. Conclusions: Acupuncture led to statistically and clinically meaningful improvements in hot flashes, endocrine symptoms, and breast cancer-specific quality of life in women undergoing adjuvant hormonal therapy for breast cancer in the USA, China and South Korea. Clinical trial information: NCT00797732, ChiCTR2100045888, KCT0003618. [Table: see text]

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

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

Abstract P1-13-06: The influence of the oncotype DX breast recurrence score on persistence to endocrine therapy in patients with low-risk ER/PR+ invasive breast cancer

Abstract Intro: The Oncotype DX breast recurrence score provides newly diagnosed patients with low-risk ER/PR+ invasive breast cancer with an estimation of their 10-year risk of distant recurrence if compliant with five years of endocrine therapy. Despite the well-established benefits of endocrine therapy, to include a decrease in local and distant disease recurrence, many patients will discontinue endocrine therapy prior to five years, defined as non-persistence. We hypothesized that the individual perception of risk of recurrence conveyed by the Oncotype DX breast recurrence score directly influences persistence with endocrine therapy and patients with higher Oncotype DX breast recurrence scores may have higher rates of persistence when compared to a similar cohort with lower recurrence scores. Further, we hypothesized that disease recurrence in women with low-risk (defined as less than 26) ER/PR+ breast cancer is due primarily to non-persistence with endocrine therapy. Methods: Our study included 198 patients with low-risk ER/PR+ breast cancer treated at a comprehensive cancer center between April 2011 and April 2014 with sufficient-follow-up data of at least 5 years. Persistence was determined by chart review and defined as a minimum duration of 55 months on endocrine therapy. Multivariable ANOVA and Fisher Chi Square Exact test were used to compare the recurrence score, 10-year risk of distant recurrence, and rates of recurrence between persistent vs non-persistent patients. Results: The average recurrence score of our cohort was 14.74 with an average 10-year risk of distant recurrence of 9.8 percent with five years of endocrine therapy. The average recurrence score was 15.24 in the persistent group vs. 13.18 for the non-persistent group (p=0.029). The average 10-year risk of distance recurrence was 10.1% in persistent patients vs 9% in non-persistent patients (p=0.019). The recurrence rate (both local and distant) was 4% in persistent patients vs 16% in non-persistent patients at 5- year follow (P=<0.01). Discussion: Non-persistence to endocrine therapy represents a major unmet need in breast cancer care. The Oncotype DX breast recurrence score significantly influences persistence to endocrine therapy as our retrospective review demonstrated that patients with low-risk ER/PR+ locally invasive breast cancer with higher Oncotype DX scores are more likely to complete the recommended 5-years of endocrine therapy. Further, despite having a lower average Oncotype DX score overall, the non-persistent group had a higher rate of recurrence when compared to the persistent group. This finding further substantiates the overall effectiveness of endocrine therapy in reducing the risk of future recurrence in patients with low-risk ER/PR+ breast cancer. Mindful framing of Oncotype DX test results by providers represents a potential avenue to increase persistence through the modulation of individual risk perception and may ultimately lead to decreased rates of disease recurrence in patients with low-risk ER/PR+ invasive breast cancer. Citation Format: Jonathan Pirruccello, Elaine Kuhn, Mary Chamberlin. The influence of the oncotype DX breast recurrence score on persistence to endocrine therapy in patients with low-risk ER/PR+ invasive 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 P1-13-06.

Abstract P5-13-07: Implications of body mass index (BMI) on the biological and clinical effects of endocrine therapy and abemaciclib in the neoadjuvant setting

Abstract Background: Our prior analysis of the MONARCH2/3 trials showed no difference in progression-free survival rates according to BMI in patients treated with abemaciclib and endocrine therapy for hormone receptor-positive, HER2-negative advanced breast cancer (Franzoi et al, JNCI 2021). However, a statistically inferior overall response rate with abemaciclib and endocrine therapy was observed in patients with BMI ≥25. In the present study, we examined the impact of baseline BMI on mean KI67% changes, achievement of complete cell cycle arrest (CCCA) and clinical and radiological responses in patients included in the phase II NEOMONARCH trial, which randomized patients to receive a 2-week initial treatment with either abemaciclib, letrozole, or abemaciclib and letrozole followed by 14 weeks of the combination of abemaciclib and letrozole as neoadjuvant therapy for hormone receptor-positive, HER2-negative early-stage breast cancer patients. Patients and methods: This is an exploratory, individual patient-level, post-hoc analysis of the NEOMONARCH study. Data was assessed through a research proposal submission in the Vivli platform. Patients were classified according to baseline BMI into underweight/normal weight (BMI <25 kg/m2) and overweight/obese (BMI≥25 kg/m2). The primary endpoint was the percent change in Ki67 expression from baseline to 2 weeks of treatment. The analysis was performed using the Fisher exact test for categorical variables and the Wilcoxon rank-sum test and its multisample generalization (Kruskal-Wallis test) for continuous variables. CCCA was analyzed as per the main study definition: patients with Ki67 % ≤2.7 after 2 weeks of treatment. Results were considered significant if p-value <0.05. Results: Out of 263 patients included in NEOMONARCH, A total of 222 patients (84.4%) had BMI information available, of whom 6 (2.7%) were underweight, 75 (33.8%) had normal weight, 77 (34.7%) were overweight and 64 (28.8%) were obese. Regarding baseline characteristics, patients with BMI ≥25 were predominantly Caucasian (p=0.001) and presented more with other histologies of breast cancer (p=0.007). There was no significant difference regarding baseline tumor grade or size, node status, ER/PR status, age, and Ki67% value at baseline according to BMI. In the overall cohort, mean Ki67% changes at 2 weeks were similar between the two BMI groups: - 19 (IQR -27.8 to -10.4) for patients with BMI <25 and -17.2 (IQR -26.8 to -11) for patients with BMI ≥25 (p=0.760). The proportion of patients achieving CCCA after 2 weeks of treatment was numerically higher for patients with BMI <25 vs ≥25 (56% vs 43%, respectively; p=0.096). Mean Ki67% reduction at 2 weeks was significantly higher for patients receiving the combination of abemaciclib + letrozole when compared to letrozole alone or abemaciclib alone, regardless of BMI. There was also no significant difference regarding radiological response (p=0.366) or clinical response (p=0.261) according to BMI at the end of the treatment period (16 weeks). Conclusions: In this exploratory analysis, BMI categorized by the threshold of 25 did not significantly impact KI67% changes or the proportion of patients achieving CCA after the initial 2 weeks of neoadjuvant therapy with abemaciclib, letrozole, or their combination. Moreover, BMI did not have an impact on radiological and clinical response rates after 14 weeks of treatment with letrozole and abemaciclib. Although limited by the small sample size, these results are reassuring that the combination of letrozole and abemaciclib appears to be active in the early setting regardless of baseline BMI. Citation Format: Maria Alice Franzoi, Matteo Lambertini, Marcello Ceppi, Marco Bruzonne, Evandro de Azambuja. Implications of body mass index (BMI) on the biological and clinical effects of endocrine therapy and abemaciclib in the neoadjuvant setting [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 P5-13-07.

Effects of Endocrine Therapy on Cognitive Function in Patients with Breast Cancer: A Comprehensive Review.

Simple SummaryMany persons diagnosed with breast cancer are treated with endocrine therapy and will experience the side effects of endocrine therapy. Cognitive adverse effects of endocrine therapy are increasingly being recognised, and can significantly affect quality of life, adherence and treatment outcome. This review aims to discuss the nature of cognitive dysfunction associated with endocrine therapy, the mechanisms underpinning its development, and evidence-based management strategies.Endocrine therapy forms the backbone of systemic therapy for the majority of persons with early and late-stage breast cancer. However, the side effects can negatively affect quality of life, and impact treatment adherence and overall oncological outcomes. Adverse effects on cognition are common, underreported and challenging to manage. We aim to describe the nature, incidence, risk factors and underlying mechanisms of endocrine therapy-induced cognitive dysfunction. We conducted a comprehensive literature review of the studies reporting on cognitive dysfunction associated with endocrine therapies for breast cancer. We also summarise prevention and treatment strategies, and ongoing research. Given that patients are taking endocrine therapies for longer durations than ever before, it is essential that these side effects are managed pro-actively within a multi-disciplinary team in order to promote adherence to endocrine therapy and improve patients’ quality of life.

The Effects of Endocrine Therapies on Lipid Profiles in Chinese Young Women With Early Breast Cancer.

This study aimed to evaluate and compare the effects of various endocrine therapies on lipid profiles in young patients with breast cancer. A retrospective, single-center study was performed to investigate the effects of tamoxifen (TAM), tamoxifen plus ovarian function suppression (TAM+OFS), and aromatase inhibitors plus ovarian function suppression (AI+OFS) on lipid profiles during the 60 months of endocrine therapy in hormone receptor-positive patients aged <40 with early breast cancer. The primary endpoint was the cumulative incidence of lipid events, and the secondary endpoints were the changes in lipid profiles. A total of 230 young patients were included with the mean age of 35.7 years old. The patients in TAM group had significantly lower incidence of 5-year lipid events than those in TAM+OFS group (7.4% versus 21.3%; P=0.016) and AI+OFS group (7.4% versus 21.6%; P=0.009). The incidence of fatty liver was significantly higher in TAM+OFS group than TAM group (52.5%versus 30.9%; P=0.043). Lipid events were associated with younger age (odds ratio (OR)=0.865, 95% confidence interval (CI): 0.780-0960; P=0.006), higher baseline LDL-C (OR=14.959, 95% CI: 4.379-51.105; P<0.001), and use of OFS (OR=3.557, 95% CI: 1.151-10.989; P=0.027). Therefore, application of OFS, with younger age and higher baseline LDL-C, may increase the incidence of lipid events in premenopausal breast cancer. More care should be taken for lipid profiles during the endocrine therapy for young breast cancer patients.

Mammographic density, endocrine therapy and breast cancer risk: a prognostic and predictive biomarker review.

Mammographic density, endocrine therapy and breast cancer risk: a prognostic and predictive biomarker review.

Влияние эндокринотерапии рака молочной железы на липидный профиль сыворотки крови женщин в постменопаузе

Актуальность. Рак молочной железы (РМЖ) занимает первое место в мире среди всех злокачественных новообразований у женщин. Удельный вес гормончувствительного РМЖ в структуре заболеваемости составляет более 60 %. Адъювантная эндокринотерапия является неотъемлемой частью послеоперационного лечения больных гормончувствительным раком молочной железы. Современные публикации свидетельствуют, что эндокринотерапия РМЖ имеет определенное влияние на уровень липидов сыворотки крови. Однако количество исследований, которые фокусируются исключительно на этой проблеме, является незначительным, а вопрос о характере влияния различных препаратов для эндокринотерапии РМЖ на липидный профиль сыворотки крови остается спорным. Значительную часть пациентов с гормончувствительным раком молочной железы составляют женщины в естественной или искусственной постменопаузе. В возрастной группе пациенток 60 лет и старше заболевания сердечно-сосудистой системы занимают первое место в структуре смертности. Благодаря современным подходам к лечению РМЖ общая выживаемость значительно увеличилась, и приобрел актуальность комплексный подход к лечению пациенток с учетом возрастной сопутствующей патологии, не менее важной с точки зрения продолжительности и качества жизни. В данной статье рассмотрено влияние наиболее распространенных средств эндокринотерапии на липидный профиль сыворотки крови, что является чрезвычайно актуальным для профилактики заболеваемости и смертности от сердечно-сосудистых событий у женщин в постменопаузе. Материалы и методы. Данная статья основана на результатах 13 клинических исследований, полученных в поисковом ресурсе PubMed по ключевым словам: «гормончувствительный рак молочной железы», «дислипидемия», «липидный профиль сыворотки», «адъювантная эндокринотерапия рака молочной железы», «селективные модуляторы эстрогеновых рецепторов» (SERM), «ингибиторы ароматазы»; клинических рекомендациях NCCN; клинических рекомендациях Европейского общества кардиологов и Европейского общества атеросклероза (ESC/EAS) по лечению дислипидемий. Результаты. SERM оказывают положительное влияние на липидный профиль сыворотки крови с некоторыми отличиями торемифена от тамоксифена (не вызывает повышения уровня триглицеридов). Ингибиторы ароматазы, по данным исследований, оказывают скорее нейтральное влияние; среди распространенных ингибиторов ароматазы летрозол оказывает наиболее выраженное негативное влияние на липидный профиль женщин в постменопаузе с гормончувствительным РМЖ. Выводы. Селективные модуляторы эстрогеновых рецепторов могут быть препаратами выбора для пациентов с высоким риском дислипидемии, кроме пациентов с изолированной гипертриглицеридемией. Использование ингибиторов ароматазы должно сопровождаться более пристальным контролем показателей липидного обмена и может потребовать дополнительного назначения гиполипидемических препаратов (статины, фибраты, секвестранты желчных кислот и т.п.). Проблема требует дальнейшего исследования с учетом внимания, уделяемого коррекции дислипидемии как средства профилактики развития заболеваний сердечно-сосудистой системы, которые являются ведущей причиной смерти в исследуемой возрастной категории.

Clinical Effect of Endocrine Therapy on Hypothyroidism

Clinical Effect of Endocrine Therapy on Hypothyroidism

Abstract 737: Estrogen receptor inhibition with tamoxifen mediates radiosensitization of ER+ breast cancer models

Abstract Purpose: Estrogen receptor (ER) expression is present in over 80% of breast tumors and has been shown to be a significant driver of tumor initiation and progression. Therefore, patients with ER-positive (ER+) breast cancers are given first-line therapies which target the ER and downstream ER signaling. Ionizing radiation (RT) has been shown to significantly improve locoregional control and increase overall survival in patients with ER+ breast cancer. Similarly, endocrine therapy (ET) has also been shown to improve metastasis-free and overall survival in women with ER+ breast cancer. While both radiation and ET are used in women with ER+ breast cancer, the effect of endocrine therapies on tumor radiosensitization remains unclear. Here we assessed the efficacy and mechanism of ER inhibition in ER+ breast cancers in combination with radiation therapy. Methods: Clonogenic survival assays were performed to assess radiosensitization and calculate radiation enhancement ratios (enhR) with the selective estrogen receptor modulator (SERM), tamoxifen, in ER+ MCF-7 and T47D cells or ER-negative (ER-) SUM-159 cells. DNA damage was assessed by yH2AX foci. Efficiency of homologous recombination (HR) or non-homologous end joining (NHEJ) was measured by RAD51 foci or using a pYFP reporter, respectively. Cell cycle effects were measured using flow cytometry with propidium iodide (PI) staining. Apoptosis was assessed by annexin V/PI via flow cytometry. Western blotting was used to quantify expression of proteins and phospho-proteins involved in DNA repair, cell cycle, and apoptosis. An MCF-7 xenograft model was used to assess the efficacy of tamoxifen with RT in vivo. Results: ER inhibition with tamoxifen radiosensitized ER+ MCF-7 (enhR: 1.14-1.50) and T47D (enhR: 1.33-1.60) cells but not ER- SUM-159 cells (enhR: 0.99-1.02). MCF-7 and T47D cells treated with tamoxifen did not have changes in the kinetics of dsDNA break repair as measured by yH2AX foci (p&amp;gt;0.05) but demonstrated a decrease in NHEJ-mediated repair (p&amp;lt;0.05). No changes were observed in HR-mediated repair by Rad51 foci (p&amp;gt;0.05). While cell cycle arrest was induced at 24 hours after RT, no changes were observed with tamoxifen treatment in combination with RT. In addition, there were no significant changes in apoptosis in MCF-7 or T47D cells with treatment of tamoxifen, radiation, or the combination (p&amp;gt;0.05). In vivo xenograft studies demonstrate a significant delay in time to tumor doubling and a significant difference in tumor growth between mice treated with tamoxifen or RT alone compared to mice treated with tamoxifen and RT. Conclusion: Our data suggest that tamoxifen may be effectively used to radiosensitize ER+ breast tumors. This work also supports further clinical investigation of the timing of radiation for patients receiving endocrine therapy as concurrent use may be more effective than sequential. Citation Format: Anna R. Michmerhuizen, Andrea M. Pesch, Rachel Schwartz, Kari Wilder-Romans, Meilan Liu, Ruth Azaria, Alexa Jelley, Lori J. Pierce, Corey W. Speers. Estrogen receptor inhibition with tamoxifen mediates radiosensitization of ER+ breast cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 737.

Impact of adjuvant endocrine therapy on prognosis in small hormone receptor-positive, HER2-negative early breast cancer.

The efficacy of adjuvant endocrine therapy for hormone receptor-positive breast cancer has been previously established. However, significant adverse events related to endocrine therapy cannot be ignored. T1 breast cancer is expected to have a good prognosis. Therefore, adjuvant endocrine therapy for T1a breast cancer patients is controversial. Thus, in this study, we examined the effect of endocrine therapy on the prognosis of T1N0 hormone receptor-positive, HER2-negative breast cancer patients in each tumor size group, and re-considered the application of endocrine therapy. We retrospectively obtained clinical and pathological data from medical records of 7635 patients who underwent surgery for breast cancer at Aichi Cancer Hospital between January 2000 and December 2017. The primary end point of our analysis was disease-free survival (DFS). The secondary end points were distant disease-free survival (DDFS), overall survival (OS), and breast cancer-specific survival (BCSS). The log-rank test, cumulative survival generated curves with Kaplan-Meier methods and the hazard ratio (HR) calculated with a Cox regression model were used to assess the effects of endocrine therapy on prognosis. The 5-year DFS was worse in the non-endocrine therapy (non-ET) group (78%) than the endocrine therapy (ET) group (95%) in the T1c population (p < 0.001, HR 0.25). However, there was no statistically significant difference in DFS between the ET and the non-ET groups in T1a (ET 96% vs non-ET 93%, p = 0.9314, HR 0.94) and T1b (ET 96% vs non-ET 93%, p = 0.1481HR 0.53) breast cancer. The OS, DDFS, and BCSS of the patients also showed that endocrine therapy was associated with improvement of the prognosis in the T1c group, but not in the T1a and T1b groups. Adjuvant endocrine therapy may be essential for T1c breast cancer patients. In contrast, this therapy should be discussed for T1a and T1b luminal breast cancer patients under some circumstances, such as suffering from adverse events.

Abstract PD5-03: Ipsilateral invasive cancer risk after diagnosis with ductal carcinoma in situ in patients with and without index surgery: The effects of endocrine therapy and radiation treatment

Abstract Background. Ongoing clinical trials are evaluating active surveillance as a potential alternative to immediate surgery in patients diagnosed with low-risk ductal carcinoma in situ (DCIS). Among women undergoing lumpectomy, the risk of ipsilateral invasive breast cancer (iIBC) after a diagnosis of DCIS can be reduced with adjuvant therapy, including endocrine therapy (ET) and radiation treatment (RT). Here we characterize the effects of ET and RT on iIBC risk after diagnosis with DCIS in a national cohort, in patients who received breast conserving surgery (BCS) within 6 months of diagnosis (BCS group) compared to patients who did not receive any locoregional treatment within 6 months of diagnosis (surveillance [SV] group). Methods. A treatment-stratified random sample of patients diagnosed with biopsy-confirmed DCIS in 2008-14 was selected from 1,330 Commission on Cancer-accredited facilities (20/site). Patients who received a mastectomy within 6 months of diagnosis were excluded. Subsequent breast events were abstracted up to 10 years after diagnosis. Primary outcomes were the population-averaged 8-year absolute risks of iIBC for the following five treatment modalities: BCS alone, SV alone, BCS + ET, SV+ET, BCS+RT, and BCS+ET+RT (where ET was defined as ≥5 years of continuous treatment). Secondary outcomes were the average treatment effects (ATE) of SV+ET vs SV, BCS+RT vs SV+ET, and BCS+RT+ET vs SV+ET. A propensity score (PS) model for treatment choice BCS vs SV was fitted with sampling design (SD) weighting and random effects for patients within facilities. Relative treatment effects (hazard ratios [HR]) for the five treatment groups were obtained using multivariable Cox proportional hazards models adjusted for tumor and patient characteristics. The models were weighted by SD and PS and included a robust sandwich covariance estimator to account for clustering of patients within facilities. Population-averaged risks and ATEs were derived from the marginal outcome probabilities: assuming that the entire population received the treatment of interest, each patient’s counterfactual probability of an iIBC event by 8 years was predicted, and then averaged across the weighted population. 95% confidence intervals (CI) were obtained by bootstrapping. Results. The final analytic cohort contained 14,245 (88.2%) BCS and 1,914 (11.8%) SV patients. Overall, median age at diagnosis was 61 years (IQR: 52-69) and median follow-up was 5.8 years (95% CI 5.7-6.1). The majority of patients were Caucasian (81.9%), with hormone receptor-positive (79.9%), and nuclear grade I/II (54.5%) DCIS. Uptake of any ET was 48.5% and 23.7% in BCS and SV patients, respectively. The relative treatment effects (HR) for the receipt of BCS, RT and ≥5 years of ET were 1.65 (95% CI: 1.14-2.39), 0.40 (95% CI: 0.27-0.61) and 0.55 (95% CI: 0.17-1.72) respectively. The 8-year population-averaged iIBC risks and corresponding ATEs are shown Table 1. Conclusion. The 8-year risk of iIBC was below 7% for all six management options. Relative and absolute treatment effects of ET and RT were comparable to previously reported estimates. In SV patients, receipt of ≥5 years of ET nearly halved the 8-year risk, indicating a substantial risk reduction potential for ET in patients who do not receive immediate surgery after diagnosis. Table 1: Population-averaged 8-year iIBC risk and ATEs.TreatmentiIBC risk (%)95% CISurveillance6.906.79-7.01Surveillance + ET3.903.83-3.96BCS4.264.21-4.31BCS + RT1.761.73-1.79BCS + ET2.392.35-2.43BCS + ET + RT0.980.96-0.99Treatment comparisonATE (%)95% CISV+ET vs SV3.02.95-3.04BCS+RT vs SV+ET2.142.11-2.17BCS+RT+ET vs SV+ET2.922.78-2.97 Citation Format: Marc D Ryser, Christel N Rushing, Samantha M Thomas, Thomas Lynch, Anne McCarthy, Zahed A Mohammed, Amanda B Francescatti, Elizabeth S Frank, Anne H Partridge, Alastair M Thompson, Terry Hyslop, E. Shelley Hwang. Ipsilateral invasive cancer risk after diagnosis with ductal carcinoma in situ in patients with and without index surgery: The effects of endocrine therapy and radiation treatment [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD5-03.