Postmenopausal Hormone Receptor-positive Breast Cancer Research Articles

Abstract 1541: Heterogeneity of the hormone receptor-positive breast tumor immune microenvironment according to patient’s body mass index

Abstract Background: Obesity is a risk factor for postmenopausal hormone receptor-positive (HR+) breast cancer (BC) and is associated with poorer outcomes. “Obesity-paradox”, a phenomenon where obesity (BMI ≥ 30) is associated with better outcomes in patients treated with immune checkpoint inhibitors (ICI), has been observed in several cancer types. It is however under-explored in BC, especially HR+ BC. Emerging data from recent trials (KEYNOTE-756 and CheckMate 7FL) have shown the potential benefits of ICI for treating early HR+ BC. This prompted the need for better insights into the biological link between obesity and HR+ BC, particularly its tumor immune microenvironment (TIME). Patients & Methods: A monocentric cohort of 33 patients (11 lean, 11 overweight, 11 obese) with early HR+ BC was selected for the study, whose tumor tissues were collected and subjected to snRNA-seq. Unsupervised clustering and cluster annotation were performed on the processed data leading to identification of cell types and subtypes. We then performed differential gene expression (DGEA) and gene set enrichment analyses (GSEA) according to BMI category for each of the immune cell types. Results: We identified a total of 76,773 immune cells belonging to six major cell types, namely B/plasma cell, dendritic cell (DC), mast cell, monocyte/macrophage (mono/macro), T cell, and natural killer (NK) cell. Their proportions varied between patients, however immune cellular composition was not associated with BMI. DGEA and GSEA revealed highly cell type-specific obesity-associated differences in the expression profile of immune cells. Notably, an enrichment of B cell-mediated immune activities, substantiated by the upregulation of Ig genes, was observed in B cells and plasma cells. This was however coupled with an overexpression of the checkpoint BTLA in B cells. CD8+ and CD4+ T cells showed a lower level of activation (higher LEF1, TCF7, lower ANXA1, IL4R), and NK cells a decreased cytokine production (CD96, CD226) and conflicting differential expression of cytotoxic molecules (lower NKG7, higher granzymes). Checkpoint genes such as PDCD1, CTLA4, TIGIT, LAG3, HAVCR2 did not show significant changes in their expression in T/NK cells. Mast cells displayed a downregulation of antigen presenting genes (CD74, HLA-A/B/E). DC and mono/macro populations also exhibited both up- and down-regulation of genes involved in different immune pathways. Conclusion: Our current data suggested that obesity was associated with multi-directional changes in the immune activities, possibly implying an unresolved inflammation in the HR+ BC tissue. Further investigation incorporating other cell types and their interaction with immune cells in both tumor and matched normal mammary tissues is warranted and on-going, which could provide more understanding of HR+ breast TIME and lead to speculation on therapeutic implications. Citation Format: Ha-Linh Nguyen, Tatjana Geukens, Maxim De Schepper, Karen Van Baelen, Marion Maetens, Gitte Zels, Amena Mahdami, Edoardo Isnaldi, Sigrid Hatse, Joke Verbeke, Christophe Matthys, Bernard Thienpont, Evy Vanderheyden, Thomas Van Brussel, Rogier Schepers, Gino Philips, Bram Boeckx, Diether Lambrechts, Giuseppe Floris, François Richard, Christine Desmedt. Heterogeneity of the hormone receptor-positive breast tumor immune microenvironment according to patient’s body mass index [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1541.

Validation of the Prognostic Performance of Breast Cancer Index in Hormone Receptor-Positive Postmenopausal Breast Cancer Patients in the TEAM Trial.

Patients with early-stage hormone receptor-positive (HR+) breast cancer face a prolonged risk of recurrence even after adjuvant endocrine therapy. The Breast Cancer Index (BCI) is significantly prognostic for overall (0-10 years) and late (5-10 years) distant recurrence (DR) risk in N0 and N1 patients. Here, BCI prognostic performance was evaluated in HR+ postmenopausal women from the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial. 3,544 patients were included in the analysis (N = 1,519 N0, N = 2,025 N+). BCI risk groups were calculated using pre-specified cutoff points. Kaplan-Meier analyses and log-rank tests were used to assess the prognostic significance of BCI risk groups based on DR. Hazard ratios (HR) and confidence intervals (CI) were calculated using Cox models with and without clinical covariates. For overall 10-year DR, BCI was significantly prognostic in Ni0 (N = 1,196) and N1 (N = 1,234) patients who did not receive prior chemotherapy (P < 0.001). In patients who were DR-free for 5 years, 10-year late DR rates for low- and high-risk groups were 5.4% and 9.3% (N0 cohort, N = 1,285) and 4.8% and 12.2% (N1 cohort, N = 1,625) with multivariate HRs of 2.25 (95% CI, 1.30-3.88; P = 0.004) and 2.67 (95% CI, 1.53-4.63; P < 0.001), respectively. Late DR performance was substantially improved using previously optimized cutoff points, identifying BCI low-risk groups with even lower 10-year late DR rates of 3.8% and 2.7% in N0 and N1 patients, respectively. The TEAM trial represents the largest prognostic validation study for BCI to date and provides a more representative assessment of late DR risk to guide individualized treatment decision-making for HR+ patients with early-stage breast cancer.

Are we there yet? Optimal duration of endocrine therapy in women with postmenopausal early-stage hormone receptor-positive breast cancer.

Are we there yet? Optimal duration of endocrine therapy in women with postmenopausal early-stage hormone receptor-positive breast cancer.

Obesity and breast cancer in women under age 40.

10536 Background: Obesity is a well-established risk factor for postmenopausal hormone-receptor positive breast cancer (BC). The role of obesity in premenopausal BC, especially in women under the age of 40, is not well understood. Multiple studies have shown a decreased rate of premenopausal BC with increasing body mass index (BMI), notably for estrogen receptor positive tumors. Even though there is an inverse association between obesity and premenopausal BC, it has been suggested that obesity has a negative prognostic role in premenopausal BC. This may be explained if premenopausal obese women develop more aggressive tumors. Obesity is associated with triple negative and Luminal B cancers in premenopausal women. We sought to evaluate the relationship between premenopausal breast cancer and obesity in a diverse patient population. Methods: We assembled a 10-year database of women diagnosed with breast cancer before age 40 in a single health system. Data collected included age at diagnosis, self-identified race, breast cancer subtype, BMI, and stage at diagnosis. The control group was all women under the age of 40 presenting to our health system in the same time period. Stratification analysis was performed using Mantel-Haenszel Risk Estimation. Results: The risk ratio between the standardized estimates of BC patients under 40 with BMI ≤ 30 to BMI &gt; 30 is 0.7924, 95% CI (0.683 – 0.920), P = 0.0022. This implies that young BC patients are more likely to be obese than all young women presenting to our health system. There are more obese Black patients compared to White patients. The effect of obesity on BC diagnosis was more pronounced in Black patients, with a risk ratio of 0.59 compared to 0.96. Conclusions: The data presented here challenge previous research which had shown that obesity seemed to be protective against breast cancer in premenopausal women. Here, we see a statistically significant increase in obesity among young women &lt; 40 years presenting with breast cancer. The increased risk of breast cancer diagnosis was particularly pronounced in obese Black women. Previous studies have had a very low proportion of Black women represented, which may cause underestimation of risk in this patient population. These data suggest that obesity is a risk factor for breast cancer in young women, especially in Black patients. [Table: see text]

Use of adjuvant bisphosphonate therapy in breast cancer by Indian oncologists: An implementation science study.

e13667 Background: Several clinical trials, expert consensus and guidelines have recommended the use of bisphosphonates (BP) in reducing the breast cancer recurrence risk in postmenopausal women. The 2019 St. Gallen Panel voted 83.7% in favour of the routine use of bisphosphonates in postmenopausal women. Similarly, the 2022 ASCO-Ontario Health guidelines for breast cancer supports the recommendation. However, the uptake of these recommendations in routine clinical practice is poorly studied. We aimed to investigate the use of adjuvant BP therapy by Indian oncologists (implementation science study). Methods: A cross sectional survey study design was used to investigate our research question. Physicians in India who treat patients with breast cancer were presented with a clinical vignette of a young woman with postmenopausal (induced) non-metastatic high risk hormone receptor-positive breast cancer. A snowball sampling strategy was employed to avoid sampling bias. Participants were requested to state their gender, primary qualification, practice setting, number of years of practice as an oncologist and proportion of patients with breast cancer in their practice. Instead of providing the option of BP therapy, we asked an open-ended question whether they would recommend any additional therapy other than surgery, radiation, chemotherapy and anti-estrogen therapy. We asked them to write in the name or class of drug if they would prescribe an additional therapy to the patient. Results: The survey was completed by 74 Oncologists. The response rate is unknown as a snowball sampling strategy was employed. Majority of the respondents were male (74%), were non-teaching private practitioners (42%), medical oncologists (62%) with up to 10 years of experience (65%), and breast cancer patients make up to 50% of their patients (84%). Most of the oncologists responded no to our question on additional therapy (76%). Of those who responded yes, only 8 suggested BP therapy (11%). Conclusions: Despite strong evidence and guidelines, adjuvant BP therapy in high-risk early breast cancer was only recommended by very few oncologists in our survey study. Steps to bridge this gap between academic research and clinical application is urgently warranted. Implementation of clinical guidelines has to be monitored routinely which may be facilitated by provider and patient surveys. This can also assist in identifying and addressing the concerns with newer recommendations.

Postoperative Adjuvant Anastrozole for 10 or 5 Years in Patients With Hormone Receptor-Positive Breast Cancer: AERAS, a Randomized Multicenter Open-Label Phase III Trial.

Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on disease-free survival (DFS). This prospective, randomized, multicenter open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients who were disease-free after treatment with either 5 years of anastrozole alone or 2-3 years of tamoxifen followed by 2-3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole for an additional 5 years or stop anastrozole. The primary end point was DFS, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with University Hospital Medical Information Network, Japan (UMIN) clinical trials registry (UMIN000000818). We enrolled 1,697 patients from 117 facilities between November 2007 and November 2012. Follow-up information was available for 1,593 patients (n = 787 in the continue group, n = 806 in the stop group), who were defined as the full analysis set, including 144 patients previously treated with tamoxifen and 259 patients who underwent breast-conserving surgery without irradiation. The 5-year DFS rates were 91% (95% CI, 89 to 93) in the continue group and 86% (95% CI, 83 to 88) in the stop group (hazard ratio, 0.61; 95% CI, 0.46 to 0.82; P < .0010). Notably, extended anastrozole treatment reduced the incidence of local recurrence (continue group, n = 10; stop group, n = 27) and second primary cancers (continue group, n = 27; stop group, n = 52). There was no significant difference in overall or distant DFS. Menopausal or bone-related all-grade adverse events were more frequent among patients in the continue group than those in the stop group, but the incidence of grade ≥3 adverse events was <1% in both groups. Continuing adjuvant anastrozole for an additional 5 years after 5 years of initial treatment with anastrozole or tamoxifen followed by anastrozole was well tolerated and improved DFS. Although no difference in overall survival was observed as in other trials, extended anastrozole therapy could be one treatment choice in postmenopausal patients with hormone receptor-positive breast cancer.

ASO Author Reflections: Inheritance of Adrenal Permissive HSD3B1 Genotype Negatively Impacts Outcomes in Hormone Receptor-Positive Postmenopausal Breast Cancer.

ASO Author Reflections: Inheritance of Adrenal Permissive HSD3B1 Genotype Negatively Impacts Outcomes in Hormone Receptor-Positive Postmenopausal Breast Cancer.

Efficacy and safety of initial five years of adjuvant endocrine therapy in postmenopausal hormone receptor-positive breast cancer: A systematic review and network meta-analysis.

535 Background: Endocrine therapy has greatly improved the clinical outcomes of hormone receptor-positive breast cancer patients. However, there was an unmet need to identify the potentially best regimen of initial adjuvant endocrine therapy. Therefore, in this network meta-analysis, we synthesized the latest evidence to indirectly compare the efficacy and safety among different 5 years of regimens of initial adjuvant endocrine therapy. Methods: We conducted a systematic search of the PubMed, Web of Science, and EMBASE in January 2022. Randomized clinical trials assessing the efficacy and safety of initial 5 years of adjuvant endocrine therapy were included. The primary outcomes were disease-free survival (DFS) and overall survival (OS) and the secondary outcome was severe adverse effects (SAEs). A Bayesian network meta-analysis was carried out to indirectly compare all regimens and the SUCRA values were used to obtain rankings. Results: Eleven studies with 49,987 subjects were included. For DFS, exemestane (EXE) (hazard ratio [HR] 0.91, 95% confidence interval [95%CI] 0.87-0.96), anastrozole (ANA) (0.94, 0.90-0.97), letrozole (LET) (0.93, 0.89-0.97), tamoxifen (TAM) followed by EXE (0.91, 0.87-0.96), and TAM followed by ANA (0.92, 0.87-0.98) were more favorable than TAM, with TAM followed by EXE ranking as the first of SUCRA. For OS, only TAM followed by ANA showed significant superiority than TAM (HR 0.91, 95%CI 0.86-0.97) and ranked as the first of SUCRA. For SAEs, EXE (HR 1.72, 95%CI 1.04-2.98), ANA (1.58, 1.03-2.43), and LET (1.63, 1.02-2.57) showed greater associations with bone fracture than TAM. However, no significant difference in the incidences of cardiac events, thromboembolic events, and cerebrovascular events was found among all comparisons. Conclusions: The sequential use of aromatase inhibitors may be the optimal treatment mode for hormone receptor-positive postmenopausal early breast cancer patients. In addition, the three kinds of aromatase inhibitors achieved roughly equal efficacy, but caused different types of SAEs.

Clinical Treatment Score post-5 years as a predictor of late distant recurrence in hormone receptor-positive breast cancer: systematic review and meta-analysis.

The Clinical Treatment Score post-5 years (CTS5) integrates four clinicopathological variables to estimate the residual disease recurrence risk in hormone receptor-positive breast cancer patients who have been treated with five years of adjuvant endocrine therapy. This study aimed to determine the accuracy of the CTS5. A systematic review was performed in accordance with the PRISMA statement. Studies relevant for inclusion in the current review were identified from The Cochrane Library, EBSCO, Ovid, PubMed, and Embase. Six papers reported on 30 354 postmenopausal patients (age range 42 to 91 years). The pooled hazard ratio (HR) of distant recurrence relative to the low-risk CTS5 category was 5.41 (95% c.i. 4.50 to 6.51; P < 0.05) for the high-risk CTS5 category and 2.32 (95% c.i. 1.90-2.84; P < 0.05) for the intermediate CTS5 category. Three papers reported on 10 425 premenopausal patients (age range 18 to 54 years). The pooled HR of distant recurrence relative to the low-risk CTS5 category was 5.42 (95% c.i. 2.26 to 13.01; P < 0.05) for the high-risk CTS5 category and 2.82 (95% c.i. 1.35 to 5.88; P < 0.05) for the intermediate CTS5 category. Relative to high-risk postmenopausal patients, the mean observed 10-year distant recurrence risk for the high CTS5 category was 13.83 per cent, which differs significantly from the CTS5 estimation of 10-year distant recurrence risk (20.3 per cent, 95% c.i. 17.2 to 24; P = 0.000). The CTS5 can predict late distant recurrence risk in pre- and postmenopausal hormone receptor-positive breast cancer patients. CTS5 overestimates the risk for high-risk patients and thus, its use in these patients warrants caution.

Overall survival with ribociclib and letrozole in advanced postmenopausal hormone receptor–positive breast cancer

Overall survival with ribociclib and letrozole in advanced postmenopausal hormone receptor–positive breast cancer

Adherence to bone health guidelines in patients with hormone receptor-positive early breast cancer: Status and clinical impact in a Swiss cohort experience

AimIn patients with postmenopausal hormone receptor-positive breast cancer (ER + eBC), aromatase inhibitors (AIs) are widely used for effective relapse prevention. However, AIs reduce bone density and increase bone-related events (BREs). Alongside calcium and vitamin D3 supplementation, bisphosphonates and denosumab are well-known options for improving outcomes in bone health and breast cancer prognosis. This study aimed to evaluate the practice patterns of bone health guideline-based management in real-world patients with ER + eBC. Material and methodsIn total, 68 patients with ER + eBC treated between 2009 and 2014 at the University Hospital Basel were included in this retrospective cohort study. Chart reviews were analyzed. Baseline, clinicopathological, treatment, and BRE data were extracted. Each patient was specifically reviewed for therapy adherence to the Swiss bone health guidelines (Swiss Association against Osteoporosis 2010 [SVGO]). ResultsThe mean patient age was 66.5 (range, 56–74) years, all post-menopausal. The most frequent tumor characteristics were tumor size of pT1–pT2 (N = 53, 77.9%) and treatment with letrozole (N = 35, 51.5%), followed by tamoxifen as a switch strategy (N = 27, 40.3%). The median treatment time with AIs was 47 (range, 30–60) months. Five patients (7.8%) experienced a fracture during or after AI treatment. Moreover, 51 (75%) patients were treated according to the SVGO recommendations. ConclusionThe fracture rate in our retrospective cohort was comparable to that in the larger phase III randomized trials. The adherence to bone health guidelines was satisfactory but still suboptimal. Clinicians should strictly adhere to the current bone health guidelines to ensure the best possible prevention of BREs and maintain bone health and cancer prognosis in patients with ER + eBC.

Obesity and Postmenopausal Hormone Receptor-positive Breast Cancer: Epidemiology and Mechanisms.

Obesity is a potential risk for several cancers, including postmenopausal, hormone dependent breast cancers. In this review, we summarize recent studies on the impact of obesity on postmenopausal women's health and discuss several mechanisms that were proposed to increase the risk of breast carcinogenesis.

118O Extended therapy with letrozole as adjuvant treatment of postmenopausal patients with early-stage breast cancer: A randomised, phase III trial of the Gruppo Italiano Mammella

The benefit of extended adjuvant therapy with aromatase inhibitors (AIs) in postmenopausal hormone-receptor positive breast cancer patients treated with tamoxifen for 2-3 years followed by an AI for 2-3 years is still controversial. We aimed to determine whether, after 2-3 years of tamoxifen, 5 years of letrozole is more effective than the standard duration of 2-3 years.

Abstract PS9-71: The effect of using adjuvant aromatase inhibitors on cognitive functions in postmenopausal women with hormone receptor-positive breast cancer

Abstract Background:Aromatase inhibitors (AIs) are used for the adjuvant treatment of early breast cancer. Although generally well-tolerated, they have some adverse effects. Because of AIs are used long term in adjuvant treatment, side effects are also very important. Preclinical and a little clinic data indicate that estrogens exert neurotrophic and neuroprotective actions in the brain. So estrogen appears to play an important role in cognitive function and memory. We know that AIs reduce circulating estrogen to very low levels. For this reason, there has been concern that these agents may have a negative effect on cognitive functions. However, this situation is still unclear. The purpose of our study is to evaluate the relationship between duration of treatment and cognitive functions in patients with breast cancer who use AIs in adjuvant therapy. Methods:Patients diagnosed with breast cancer who use AIs as adjuvant treatment and followed up at the Akdeniz University Medical Oncology Clinic were included. The patients were surveyed for demographic characteristics. Montreal Cognitive Assessment (MoCA) and Standardized Mini-Mental State Examination (SMMT) tests were applied to patients by the same investigator to evaluate their cognitive functions. The total scores of the tests and the orientation, naming, short-time memory, visuospatial functions-executive functions, attention, abstract thinking, language which are the MoCA subscales were evaluated separately. In the Turkish population, the normal range of the MoCA and SMMT tests are 21-30 points and 24-30 points, respectively. Patients were grouped as 0-6, 6-12, 12-24, 24-36, 36 and more months according to the duration of AIs using time. 200 patient’s data were analyzed with SPSS package program. This study was approved by the Akdeniz University Faculty of Medicine Clinical Research Ethnics Committee and was conducted in accordance with declaration of Helsinki. Results:The median follow-up time was 55.5 months. The median duration of AIs treatment was 36.5 months. The mean age of patients was 61.3 years-old. There was no relationship between duration of treatment and MoCA and SMMT scores which indicates cognitive functions (p&amp;gt;0.05). In addition, no statistically relationship was found in the evaluation of MoCA subscales (p&amp;gt;0.05). As expected, the total MoCA and SMMT scores were affected by factors such as age, education level, and employment status. Interestingly, although it was not our main purpose, a causal relationship between the presence of hypertension and cognitive decline was shown in our study (p: 0.004). A statistically strong correlation was found between the MoCA and SMMT scores. So, our data are reliable. The duration of treatment with AIs and MoCA and SMMT scores of the patients were given in Table 1. Conclusions:As a result, despite conflicting results in the literature, we showed with 200 patients that adjuvant treatment with AIs does not affect cognitive functions in post-menopausal hormone receptor-positive breast cancer patients. Table 1: Relationship between the duration of treatment with AIs and MoCA and SMMT scoresDuration of AInMoCA*Mean±SDMoCAMed (min-max)SMMT**Mean±SDSMMTMed (min-max)0-6 m2319,7±5,221 (10-26)25±425 (15-30)6-12 m2420,7±5,421,5 (8-28)24,7±3,624 (16-30)12-24 m1418,2±4,118,5 (13-27)24,3±425 (13-29)24-36 m2920,3±4,920 (11-29)24,1±3,225 (17-30)36 m and more11020,3±4,521 (8-29)25±3,225 (14-30)Total20020.1±4,721 (8-29)24,8±3,425 (13-30)AI: Aromatase inhibitors, m: Mounths, n: Number, MoCA: Montreal Cognitive Assessment, SMMT: Standardized Mini-Mental State Examination, SD: Standart Deviation, Med: Median*p: 0.550 **p:0.533 Citation Format: Rukiye Guler Ilhan, Yusuf Ilhan, Sema Sezgin Goksu, Ali Murat Tatli, Hasan Senol Coskun. The effect of using adjuvant aromatase inhibitors on cognitive functions in postmenopausal women with hormone receptor-positive breast cancer [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 PS9-71.

Postoperative Adjuvant Anastrozole for 10 Rather than 5 Years in Patients with Oestrogen Receptor-Positive Breast Cancer: AERAS, a Randomised Multicentre Open-Label Phase III Trial

Background: Treatment with an aromatase inhibitor for 5 years is the standard treatment for postmenopausal hormone receptor-positive breast cancer. We investigated the effects of extending this treatment to 10 years on the risk of breast cancer recurrence. Methods: This prospective, randomised, multicentre open-label phase III study assessed the effect of extending anastrozole treatment for an additional 5 years in postmenopausal patients with stage I–IIIA hormone receptor-positive breast cancer who were disease-free after treatment with either 5 years of anastrozole alone or 2–3 years of tamoxifen followed by 2–3 years of anastrozole. Patients were allocated randomly (1:1) to continue anastrozole (1 mg/day orally) for an additional 5 years or stop anastrozole, using the central computer at the Comprehensive Support Project for Oncology Research Data Centre. Randomisation was stratified by type of postoperative endocrine therapy, nodal status, prior adjuvant chemotherapy, and facility. The primary endpoint was disease-free survival, including breast cancer recurrence, second primary cancers, and death from any cause. This study is registered with UMIN clinical trials registry, number UMI00818. Findings: We enrolled 1697 patients from 117 facilities between November 2007 and November 2012. Patients were assigned randomly to the continue group (n=849) or the stop group (n=848). Follow-up information was available for 1593 patients (n=787 in the continue group, n=806 in the stop group) as the full analysis set. After a median follow-up of 5·1 years, there were 172 events involving disease recurrence or the occurrence of contralateral breast cancer (75 in the continue group and 97 in the stop group) and 40 deaths (21 in the continue group and 19 in the stop group). The 5-year disease-free survival rates were 91% (95% confidence interval [CI] 89–93) in the continue group and 86% (95% CI 83–88) in the stop group (hazard ratio [HR] for disease-free survival 0·61, 95% CI 0·46–0·82; p<0·0010, two-sided log-rank test). The 5-year overall survival rates were 98% in the continue group and 98% in the stop group (HR 1·13, p=0·7042). The 5-year distant disease-free survival rates were 95% in the continue group and 93% in the stop group (HR 0·68, p=0·0553). Sixty-seven second primary cancers occurred, including 24 in the continue group and 43 in the stop group. Menopausal or bone-related all-grade adverse events were more frequent among patients in the continue group than in the stop group, including higher incidences of hot flashes (111 [14%] vs 81 [10%]), stiff joints (162 [21%] vs 98 [12%]), arthralgia (294 [37%] vs 236 [29%]), and new-onset osteoporosis (370 [47%] vs 355 [44%]). Interpretation: Continuing adjuvant anastrozole for an additional 5 years after 5 years’ initial treatment with anastrozole or tamoxifen is safe and beneficial in postmenopausal patients with hormone receptor-positive breast cancer. Trial Registration: This study is registered with UMIN clinical trials registry, number UMI00818. Funding: The Comprehensive Support Project for Oncology Research of the Public Health Research Foundation Declaration of Interest: None to declare. Ethical Approval: Ethical approval was provided by local ethics committees in each hospital.

The Association between Obesity and Premenopausal Breast Cancer According to Intrinsic Subtypes - a Systematic Review.

Introduction Obesity is a well-established risk factor for postmenopausal hormone-receptor positive breast cancer. The relationship between premenopausal breast cancer intrinsic subtypes and obesity is not completely elucidated; therefore, this systematic review was conducted to give an overview about the existing evidence. Methods This review followed the PRISMA Statement for Systematic Reviews and Meta-analyses. Full electronic search was conducted in PubMed and Orbis for articles published in English between January 2008 and June 2018. The literature search was performed in June 2018 using search strings that combined the Medical Subject Headings (MeSH terms) keywords and/or text words in any field were used: “body mass index” (BMI) OR obesity OR overweight AND premenopausal breast cancer. Results 391 articles were found to be eligible, of which ultimately 21 were included comprising a total of 55 580 breast cancer patients. 45% were case-control studies, 35% were single cohort studies, 15% were cohort studies, two were cross-sectional studies, one was a multicenter-study and one was a pooled analysis. The evidence shows a tendency for an increased risk for the more aggressive triple negative breast cancer subtype in obese premenopausal women and a decreased risk for less aggressive tumor subtypes such as the luminal A subtype. The evidence is limited by small sample sizes for triple negative and HER2-positive subtypes in severely obese patients. Conclusion Higher BMI might influence aggressive tumor characteristics among premenopausal women and has divergent impacts on the risk of different breast cancer subtypes. Further research is needed to confirm these results and to evaluate potential pathophysiologic mechanisms for the relationship between obesity and aggressive premenopausal breast cancer subtypes.

Association of CYP19A1 gene variations with adjuvant letrozole-induced adverse events in South Indian postmenopausal breast cancer cohort expressing hormone-receptor positivity.

Musculoskeletal adverse events (MS-AEs) and vasomotor symptoms (VMSs) are the major side-effects of newer generation non-steroidal aromatase inhibitor (AI), letrozole. Single-nucleotide polymorphisms (SNPs) in CYP19A1 gene coding for the enzyme aromatase are related to AI treatment-associated adverse drug reactions. Therefore, we aimed to determine whether SNPs in the CYP19A1 gene are associated with adjuvant letrozole-induced 'specific' AEs in postmenopausal hormone receptor-positive (HR+) breast cancer patients. Genomic DNA was isolated from 198HR+ breast cancer patients by the phenol-chloroform method, and eleven SNPs in the CYP19A1 gene were genotyped by TaqMan genotyping assays on the qRT-PCR system. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0, and the data were analyzed using SPSS v19.0 and Haploview v4.2 statistical software. Subjects carrying the genetic variants of CYP19A1 gene SNP rs700519 had significantly higher odds (OR 2.33; 95% CI [1.29-4.20], P = 0.0057) of MS-AEs under dominant statistical effect. The frequency of the two distinct haplotypes that include the variant allele 'T' at rs700519 locus, H5-GCTATCTGGCG (P = 0.042) and H11-GCTATTGCACG (P = 0.013) were significantly higher in patients with musculoskeletal toxicity than in those without MS-AEs and thus predisposing to MS-AEs. Similarly, H6-GCCAGCTGGCG (P = 0.037) haplotype exhibited higher frequencies in patients presented with VMSs. However, no such association was observed between CYP19A1 genotypes and VMSs. To the best of our knowledge, this is the first study assessing the impact of CYP19A1 genetic variations with adjuvant letrozole treatment-associated AEs in Indian women. Genetic variations in the CYP19A1 gene is associated with letrozole-induced AEs and warrants further investigation in larger cohorts to validate this finding.

Association of adjuvant aromatase inhibitor with cataract risk in postmenopausal women with breast cancer.

BackgroundAromatase inhibitor (AI) is a cornerstone drug for endocrine therapy of postmenopausal hormone receptor-positive breast cancer. The relationship between AI medication and subsequent cataract risk is yet inconclusive.MethodsA total of 1,697 postmenopausal, early-staged, and hormone receptor-positive breast cancer patients from the prospectively-maintained database of the Breast Surgery Department at Fudan University Shanghai Cancer Center were included, with 542 patients received no endocrine therapy and 1,155 treated with AI only. We explored the influence the use of AI or not and the duration of AI on the subsequent incidence of cataract.ResultsA total of 146 (8.6%) cataracts were observed in the whole study population. The incidence of cataract is highly related to age, with incidence of cataract in patients <50 years old, 50–60 years, ≥60 years was 2.9%, 6.9%, and 13.3%, respectively (P<0.001). There was no significant relationship between adjuvant AI use and cataract (7.4% in no endocrine group vs. 9.2% in the AI group) with an adjusted hazard ratio of 1.20 (95% confidence interval: 0.8–1.7, P=0.30). The incidence of cataract in patients with long-term AI (more than 5 years) could be high up to 14.7%, but without statistical significance compared to those the shorter duration (P=0.52).ConclusionsThere is no significant association between use of AI and cataract in postmenopausal breast cancer patients. Of note, age is an important risk factor for cataract and it is necessary to surveil the eye health in postmenopausal elderly women.

Abstract P1-08-01: Estrogen-induced cell cycle arrest and apoptosis in aromatase inhibitor-resistant breast cancer: Insights from single cells analysis of a patient-derived xenograft model

Abstract Background: Estradiol (E2) is known to promote breast cancer. However, several small-scale prospective clinical trials reported the unexpected therapeutic benefit of E2 for aromatase inhibitor (AI)- resistant cases of hormone receptor-positive postmenopausal breast cancer. Considering that the practicality and safety of E2 treatments are still undefined, the objective of this study is to uncover the mechanisms of E2-induced tumor regression, which will lead to a better design of E2 therapies. Methods: While most of our ER+ breast cancer patient-derived xenograft (PDX) models are positively regulated by E2, an estrogen-suppressive model (named GS3) was established from an AI resistant ER+/PR−/HER2− brain metastatic breast cancer. E2 pellets (1mg each) or placebo pellets were implanted in mice carrying GS3 for in vivo drug efficacy examination. Beside tumor growth response, immunohistochemistry (IHC), RNA sequencing, and reverse phase protein array (RPPA) analyses of PDX specimens were conducted to decipher molecular changes after E2 treatments. Importantly, since the cancer tissue has a very heterogeneous structure, the single-cell analysis was further performed to examine gene expression profiles in individual cells. In addition, in vitro cell proliferation analysis was carried out using organoids from GS3. Results: E2 inhibited the growth of GS3 both in vivo and in vitro. ERα and ERβ genes in GS3 are wild-type and not amplified. ERα is involved because E2-mediated inhibition of GS3-organoids can be reversed by the co-treatment of ERα antagonist (MPP), not by ERβ antagonist (PHTPP). IHC showed that PR expression appeared, Ki-67 and CEACAM5 (CEA) expressions decreased, and the number of apoptotic cells significantly increased after E2 treatment. RNA sequencing indicated that estrogen-regulated genes, e.g., PGR, EGR3, PDZK1, and GREB1, were up-regulated, while tumor growth was repressed by E2. Single cell RNAseq analysis demonstrated that cells from E2-treated and Placebo-treated tumors were placed in different clusters based on principle component analysis of Highly Variable Genes (HVGs). Importantly, after one-week, many cells of E2-treated PDXs were arrested within the G1 phase of the cell cycle (G1, 60%; S, 19%; G2M, 21%), whereas, cells of placebo-treated samples advanced to the S and G2M phases (G1, 47%; S, 27%; G2M, 26%). Gene Set Variation Analysis of cells from E2-treated PDXs revealed enrichment of genes associated with reactive oxygen species (ROS) mechanism. E2 increased cells expressing pro-apoptotic genes, such as TP53, BOK,IL24, and PGLYRP2. Gene expressions including mitogen-activated protein kinase (MAPK) signaling pathway, such as GADD45A, MAP3K5 (ASK1), MAPK9 (JNK2), and especially MAPKAPK2 were also increased in E2 treated PDXs. Conclusions: E2/ERα-mediated suppression of GS3 tumor growth was accompanying the inhibition of the cell cycle progression and increased expression of pro-apoptotic genes. It is known that classical MAPK pathway induces cell proliferation, meanwhile, JNK MAPK pathway induces p53 signaling pathway and apoptosis. We hypothesize that E2 induces ROS and promotes apoptosis of GS3 due to JNK MAPK pathway activation. This could be an unexpected outcome of AI resistance. Using this valuable estrogen-down-regulated ER+ breast cancer PDX and informative integrative omics analyses, critical molecular mechanisms on E2-mediated apoptosis are being revealed in our laboratory. The ongoing research using E2-sensitive PDXs will identify key markers to select AI resistant patients who are expected to respond effectively to estrogen-induced apoptosis treatments as well as to evaluate the efficacy of drug combination with estrogen, including CDK 4/6 inhibitors. Citation Format: Hitomi Mori, Kohei Saeki, Gregory Chang, Xiwei Wu, Pei-Yin Hsu, Noriko Kanaya, George Somlo, Shiuan Chen. Estrogen-induced cell cycle arrest and apoptosis in aromatase inhibitor-resistant breast cancer: Insights from single cells analysis of a patient-derived xenograft model [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-08-01.

First-line endocrine therapy for postmenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer: a systematic review and meta-analysis

BackgroundIn establishing the 2018 Breast Cancer Practice Guidelines of the Japan Breast Cancer Society, we explored the optimal first-line endocrine therapy for advanced postmenopausal hormone receptor-positive breast cancer.MethodsWe performed a systematic review of relevant reports from randomized-controlled studies published prior to November 2016 found using medical journal search engines. The main outcomes which we evaluated were progression-free survival (PFS), objective response rate (ORR), disease control rate (CBR), and toxicity.ResultsFour controlled trials comparing aromatase inhibitors (AI) and cyclin-dependent kinase (CDK)4/6 inhibitor combination therapy to AI monotherapy, and two controlled trials comparing anastrozole to fulvestrant 500 mg were analyzed. AI/CDK4/6 inhibitor combination therapy significantly improved PFS (Risk Ratio: 0.67, 95%CI 0.60–0.73), increased ORR (Risk Difference: 0.11, 95% CI 0.07–0.16), and increased CBR (Risk Difference: 0.11, 95% CI 0.07–0.15), compared with AI monotherapy. Patients who received this combination therapy had a higher grade ≥ 3 adverse event rate more than those who received AI monotherapy (Risk Difference: 43%, 95%CI: 0.39–0.47). Fulvestrant 500 mg alone significantly improved PFS (risk ratio: 0.85, 95%CI 0.72–0.98), but ORR and CBR were similar to those of anastrozole alone.ConclusionIn the first-line treatment for advanced postmenopausal hormone receptor-positive breast cancer, a combination therapy of CDK4/6 inhibitors and AI showed significant improvement of PFS, ORR, and CBR but with significant increased toxicities compared with AI alone. Fulvestrant 500 mg monotherapy significantly prolonged PFS compared with AI monotherapy. We must wait for the results of the studies with longer follow-up period.