Hormone-sensitive Breast Cancer Research Articles

Effect of first-line endocrine therapy in patients with hormone-sensitive advanced breast cancer: a network meta-analysis [Corrigendum

[This corrects the article on p. 2647 in vol. 11, PMID: 29780257.].

Abstract 4834: CT7001: An orally bioavailable CDK7 inhibitor is a potential therapy for breast, small-cell lung and haematological cancers

Abstract CDK7 inhibition has emerged as a promising strategy in a range of cancer indications. CDK7 acts as a regulator of transcription through its role in phosphorylating and activating RNA Polymerase II (polII) as well as a master regulator of the cell cycle through phosphorylation of members of the CDK family. Inhibition of CDK7 in cancer cells has been shown to be effective in blocking transcriptional addiction to a defined cluster of genes (Wang et al 2015) and leads to decreased cell cycling, a decrease in the levels of proto-oncogenes such as c-Myc and induction of apoptosis. Here we describe the properties of a potent, selective and orally bioavailable CDK7 inhibitor CT7001 (formerly known as ICEC0942). Profiling across a pan-cancer cell line panel showed that CT7001 has anti-proliferative activity in a range of cancer types including acute myeloid leukaemia (AML), small cell lung (SCL) and hormone sensitive and triple negative breast cancers (TNBC).Mechanistic investigations revealed that CT7001s activity was associated with both a decrease in cell proliferation and an induction of apoptosis. Inhibition of cell proliferation was commensurate with a decrease in the levels of c-Myc, Mcl-1 and phospho-Pol II as determined by Western Blot analysis.CT7001 was then evaluated in a range of pre-clinical cancer models. CT7001 was shown to lead to cell death in a panel of patient derived models of small-cell lung cancer (SCLC) in 3D spheroid assays. In an in vivo orthotopic-patient derived xenograft model of TNBC in nu/nu mice, orally administered CT7001 monotherapy produced strong and sustained regression of the tumour that persisted during the dosing schedule, and strong suppression was still maintained upon cessation of treatment. At doses that produced regression CT7001 was well tolerated with little effect on body weight (<10%). Similarly, CT7001 produced a near complete regression in an MV-4-11 xenograft model of AML. Pre-clinical toxicity studies in rat and dog demonstrated that CT7001 was well tolerated at biologically active doses, with no evidence for neutropenia that is associated with inhibitors of other members of the CDK family.Taken together these studies indicate CT7001 is a potent, selective and orally bioavailable inhibitor of CDK7 that shows excellent promise as a potential new treatment in a number of oncology indications. A Phase I study to explore the safety and tolerability of CT7001 was initiated in November 2017. Reference: Wang et al Cell. 2015 163(1):174-86 Citation Format: Edward K. Ainscow, Andrew Leishman, Elaine Sullivan, Bo Li, William Gallagher, Adam Peall, Kristopher Clark, Stuart Thomson, Simak Ali, Raoul C. Coombes, Ash Bahl. CT7001: An orally bioavailable CDK7 inhibitor is a potential therapy for breast, small-cell lung and haematological cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4834.

PO-258 Can we treat early breast cancer without surgery? Is primary definitive hormone therapy a valid alternative for operable hormone sensitive breast cancer?

IntroductionPre-clinical, epidemiological and randomised data support the hypothesis that aspirin has the potential to be an effective adjuvant cancer therapy. Neoadjuvant (NA) therapy is the best way to study a drug´s action in a tumour and in a tumour’s microenvironment. Aspirin is yet to be studied in the NA setting in breast cancer (BC).Material and methodsWe have designed an interventional project included in the HoTBreast trial: the extended use of HT as an NA for breast cancer patients who refuse surgery or are considered inadequate to receive it, in the context of close surveillance. In this group of extended NA treatment patients,different hormone treatment strategies (aromatase inhibitor and tamoxifen) are allowed to be used, depending on tumour response and patient quality of life.During treatment, clinical and imaging (ultrasound) follow-up will be implemented every two to three months in the first 3 years and every four to six months after that. The treatment option can be changed at any time if considered appropriate, based on disease response or progression and the patient’s quality of life. This group will be randomly divided into two subgroups, one who willreceive hormone treatment alone and a second one who will receive HT and aspirin. Aspirin plays the role of an anti-inflammatory controller and it is not clear what the relation between chronic inflammation processes and breast cancer is – this is a new approach for cancer treatment with a strategy targeting the tumour microenvironment. Our secondary objective is to understand if the local disease presents the same response as the systemic one (in cases where this also exists) or if it can be used as an independent predictor of disease behaviour.Results and discussionsWe believe that HoTBreast Trial can give some answers about the best practice for treating early BC. We also expect that it can shed some light on the question of the role of surgery in early BC and the use of aspirin in BC patients. We acknowledge the hypothesis that aspirin can improve the treatment of BC patients in a safe, well tolerated and inexpensive way.ConclusionEfforts should be made to better communicate to patients that NA HT is a valid option and sometimes the most appropriate for the specific patient. The decision should depend on the patient, based on an informed understanding of the benefits and risks of avoiding surgery.

Abstract 948: Preventing estrogen receptor alpha-positive breast cancer outgrowth with the use of hormone replacement therapy

Abstract Menopause occurs in all women, usually between the ages of 45 and 55. As a result of menopause, women often experience undesirable vasomotor symptoms, which can be alleviated by hormone replacement therapy (HRT). The Women's Health Initiative (WHI) trial concluded that PremPro, a HRT formulation that combines conjugated equine estrogens (CE) with medroxyprogesterone acetate, increases the risk of breast cancer. Over the years, the number of women taking HRT has dramatically decreased due to the perceived risk based largely on the results of the WHI trial. Follow-up sudies suggest that breast cancer cases from PremPro treatment were primarily due to the outgrowth of occult tumors, not the formation of new disease. Duavee, a more recent form of HRT that combines CE and bazedoxifene (BZA), a selective estrogen receptor modulator (SERM) and degrader (SERD), has been approved by the FDA for treatment of moderate to severe hot flashes and to reduce the risk of osteoporosis. More importantly, this CE+BZA mixture not only relieves symptoms associated with menopause, but it also does not stimulate the breast or uterus. Several preclinical studies suggest that CE+BZA might be protective in the breast, however the mechanism of action of this new combination therapy is not known. Our goal, therefore, is to elucidate the underlying molecular mechanisms by which CE+BZA differentially affects estrogen receptor alpha (ERα) action in the mammary gland, using transcriptome and whole genome occupancy analysis in breast cancer cell lines. RNA-Seq and ChIP-Seq studies suggest that CE+BZA decreases pathways related to S-phase entry, cell cycle regulation and BRCA1. We are also studying the effects of CE+BZA on early mammary cancer progression in the estrogen-sensitive polyoma middle T antigen (PyMT) transgenic mouse model and have observed that treatment with CE+BZA delayed the onset of tumors and decreased their rate of growth. Mice treated with CE+BZA also survived longer. In addition, CE+BZA was able to decrease the rate of tumor growth in an ERα-positive patient-derived xenograft (PDX) mouse model. An improved understanding of the molecular mechanisms of CE+BZA action in hormone sensitive breast cancer cell and animal models should have important implications for women considering HRT. Citation Format: Anna G. Dembo, Emily S. Aledort, Geoffrey L. Greene. Preventing estrogen receptor alpha-positive breast cancer outgrowth with the use of hormone replacement therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 948.

Women's Beliefs on Early Adherence to Adjuvant Endocrine Therapy for Breast Cancer: A Theory-Based Qualitative Study to Guide the Development of Community Pharmacist Interventions.

Adjuvant endocrine therapy (AET) taken for a minimum of five years reduces the recurrence and mortality risks among women with hormone-sensitive breast cancer. However, adherence to AET is suboptimal. To guide the development of theory-based interventions to enhance AET adherence, we conducted a study to explore beliefs regarding early adherence to AET. This qualitative study was guided by the Theory of Planned Behavior (TPB). We conducted focus groups and individual interviews among women prescribed AET in the last two years (n = 43). The topic guide explored attitudinal (perceived advantages and disadvantages), normative (perception of approval or disapproval), and control beliefs (barriers and facilitating factors) towards adhering to AET. Thematic analysis was conducted. Most women had a positive attitude towards AET regardless of their medication-taking behavior. The principal perceived advantage was protection against a recurrence while the principal inconvenience was side effects. Almost everyone approved of the woman taking her medication. The women mentioned facilitating factors to encourage medication-taking behaviors and cope with side effects. For adherent women, having trouble establishing a routine was their main barrier to taking medication. For non-adherent women, it was side effects affecting their quality of life. These findings could inform the development of community pharmacy-based adherence interventions.

Role of adding ovarian function suppression to tamoxifen in young women with hormone-sensitive breast cancer who remain premenopausal or resume menstruation after chemotherapy: The ASTRRA study.

502Background: The role of adding ovarian function suppression (OFS) to tamoxifen (T) for premenopausal patients with breast cancer after completing (neo) adjuvant chemotherapy is uncertain. The pr...

Long-term outcomes in women with low-risk hormone-sensitive early-stage breast cancer.

e12583Background: Oncotype DX test is useful in the identification of women who have a low risk of recurrence and can safely avoid chemotherapy. However, there are persistent gaps in knowledge on t...

Dependence receptor UNC5A restricts luminal to basal breast cancer plasticity and metastasis

BackgroundThe majority of estrogen receptor-positive (ERα+) breast cancers respond to endocrine therapies. However, resistance to endocrine therapies is common in 30% of cases, which may be due to altered ERα signaling and/or enhanced plasticity of cancer cells leading to breast cancer subtype conversion. The mechanisms leading to enhanced plasticity of ERα-positive cancer cells are unknown.MethodsWe used short hairpin (sh)RNA and/or the CRISPR/Cas9 system to knockdown the expression of the dependence receptor UNC5A in ERα+ MCF7 and T-47D cell lines. RNA-seq, quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, and Western blotting were used to measure the effect of UNC5A knockdown on basal and estradiol (E2)-regulated gene expression. Mammosphere assay, flow cytometry, and immunofluorescence were used to determine the role of UNC5A in restricting plasticity. Xenograft models were used to measure the effect of UNC5A knockdown on tumor growth and metastasis. Tissue microarray and immunohistochemistry were utilized to determine the prognostic value of UNC5A in breast cancer. Log-rank test, one-way, and two-way analysis of variance (ANOVA) were used for statistical analyses.ResultsKnockdown of the E2-inducible UNC5A resulted in altered basal gene expression affecting plasma membrane integrity and ERα signaling, as evident from ligand-independent activity of ERα, altered turnover of phosphorylated ERα, unique E2-dependent expression of genes effecting histone demethylase activity, enhanced upregulation of E2-inducible genes such as BCL2, and E2-independent tumorigenesis accompanied by multiorgan metastases. UNC5A depletion led to the appearance of a luminal/basal hybrid phenotype supported by elevated expression of basal/stem cell-enriched ∆Np63, CD44, CD49f, epidermal growth factor receptor (EGFR), and the lymphatic vessel permeability factor NTN4, but lower expression of luminal/alveolar differentiation-associated ELF5 while maintaining functional ERα. In addition, UNC5A-depleted cells acquired bipotent luminal progenitor characteristics based on KRT14+/KRT19+ and CD49f+/EpCAM+ phenotype. Consistent with in vitro results, UNC5A expression negatively correlated with EGFR expression in breast tumors, and lower expression of UNC5A, particularly in ERα+/PR+/HER2− tumors, was associated with poor outcome.ConclusionThese studies reveal an unexpected role of the axon guidance receptor UNC5A in fine-tuning ERα and EGFR signaling and the luminal progenitor status of hormone-sensitive breast cancers. Furthermore, UNC5A knockdown cells provide an ideal model system to investigate metastasis of ERα+ breast cancers.

Effect of first-line endocrine therapy in patients with hormone-sensitive advanced breast cancer: a network meta-analysis.

BackgroundEndocrine therapy is the cornerstone treatment for patients with hormone receptor-positive advanced breast cancer. We aimed to assess the effectiveness of various first-line endocrine monotherapies or combinations to determine the optimal sequence in a network meta-analysis.Materials and methodsWe searched PubMed, EMBASE, and the Cochrane Library for randomized controlled trials (RCTs) from inception up to November 21, 2017. We included only RCTs that assessed the effectiveness of the following treatments as a monotherapy or in combination as the first-line treatment: tamoxifen, anastrozole, letrozole, exemestane, fulvestrant, palbociclib, and ribociclib. The results were presented with pooled odds ratio or hazard ratio (HR), and 95% credible interval (CrI). The primary outcomes were objective response rate (ORR) and progression-free survival/time to progression.ResultsA total of 16 eligible articles (14 RCTs) involving 6,602 patients treated with 10 different first-line endocrine therapies were assessed in our network meta-analysis. Palbociclib plus letrozole was superior to anastrozole, letrozole, exemestane, fulvestrant 500 mg, and anastrozole plus fulvestrant (loading dose) (HR=0.44, 95% CrI: 0.33–0.58; HR=0.56, 95% CrI: 0.45–0.68; HR=0.45, 95% CrI: 0.32–0.61; HR=0.58, 95% CrI: 0.42–0.81; HR=0.50, 95% CrI: 0.37–0.68; respectively). However, there is no significant advantage compared with ribociclib plus letrozole (HR=1.00, 95% CrI: 0.72–1.39). In terms of ORR, ribociclib plus letrozole is more effective than palbociclib plus letrozole (odds ratio=1.30, 95% CrI: 0.83–2.02).ConclusionPalbociclib plus letrozole and ribociclib plus letrozole might be the optimal first-line endocrine therapeutic choices for hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer due to a longer progression-free survival/time to progression and a more efficacious ORR.

ER-positive breast cancer cells are poised for RET-mediated endocrine resistance.

The RET tyrosine kinase signaling pathway is involved in the development of endocrine resistant ER+ breast cancer. However, we know little about how ER+ cells activate RET signaling and initiate an endocrine resistant phenotype. Here we show that both ER+ endocrine resistant and sensitive breast cancers have a functional RET tyrosine kinase signaling pathway, but that endocrine sensitive breast cancer cells lack RET ligands that are necessary to drive endocrine resistance. Transcription of one RET ligand, GDNF, is necessary and sufficient to confer resistance in the ER+ MCF-7 cell line. Endogenous GDNF produced by endocrine resistant cells is translated, secreted into the media, and activates RET signaling in nearby cells. In patients, RET ligand expression predicts responsiveness to endocrine therapies and correlates with survival. Collectively, our findings show that ER+ tumor cells are “poised” for RET mediated endocrine resistance, expressing all components of the RET signaling pathway, but endocrine sensitive cells lack high expression of RET ligands that are necessary to initiate the resistance phenotype.

Duloxetine for AI-associated joint pain in breast cancer patients

Aromatase inhibitors (AIs) are the standard of care for treatment of both early and advanced hormone-sensitive breast cancer in postmenopausal women. Although AIs have been considered to be well-tolerated, only 50 % of patients can complete the full course of the treatment, at the optimal schedule (1).

Primary endocrine therapy in elderly women with hormone sensitive breast cancer: disease response and clinical benefit outcomes

Primary endocrine therapy in elderly women with hormone sensitive breast cancer: disease response and clinical benefit outcomes

Abstract P2-11-01: Effects of radiotherapy on breast cancer outcomes among stage I, low-Recurrence risk, hormone-Sensitive breast cancer: Pooled analysis of individual data from phase III trials

Abstract Purpose: Radiotherapy after breast conservation has become the standard of care. Prior meta-analyses of radiotherapy benefits pre-dated availability of gene expression profiling (GEP) to assess recurrence risk and/or did not include all relevant outcomes. This analysis utilized GEP information with individual-level data from seven clinical trials to evaluate the impact of omitting radiotherapy on recurrence and mortality. Patients and Methods: The pooled observational data included women who had undergone breast conservation surgery for stage I, ER+ and/or PR+/HER2- cancers with clinicopathologically estimated 21-Gene Recurrence Scores (RS) of ≤ 18, and did not receive chemotherapy (n= 1,684). The primary endpoint was 10-year invasive or DCIS recurrence free-interval (IRFI-DCIS), including breast cancer death and was estimated using adjusted Cox models. Secondary outcomes were breast-cancer specific and all-cause survival. Covariates included for all models were age, tumor size, grade, hormonal status, type of hormonal therapy, risk score, and trial. Results: Ten-year IRFI-DCIS was high (96.6% with radiotherapy vs. 91.6% without), for an absolute difference of 5%. Omission of radiotherapy (vs. radiotherapy) was associated with an overall adjusted hazard ratio of 2.6 (95% confidence interval 1.5-4.5) for any first event. There was only a significant increase in risk of loco-regional; not, distant recurrence, breast cancer–specific or overall survival. The effect of radiotherapy varied across subgroups, with lower first event rates for those with estimated RS of <11 (vs. 11-18), and women ages 60+ (vs. <60 years). Conclusion: Omission of radiotherapy in hormone-sensitive patients with low recurrence risk may lead to a modest absolute increase in loco-regional recurrence, but does not appear to increase risk of distant recurrence or death. Citation Format: Jayasekera JC, Schechter C, Jagsi R, White J, Chapman J-AW, Whelan T, Sparano JA, Anderson SJ, Fyles A, Sauerbrei W, Zellars RC, Li Y, Song J, Julian T, Berry D, Feuer EJ, Luta G, Mandelblatt JS. Effects of radiotherapy on breast cancer outcomes among stage I, low-Recurrence risk, hormone-Sensitive breast cancer: Pooled analysis of individual data from phase III trials [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-01.

Abstract P5-21-22: Palbociclib in highly pretreated metastatic ER-positive HER-2 negative breast cancer

Abstract Palbociclib, a first-in-class CDK 4/6 inhibitor, in combination with letrozole or fulvestrant is now licensed for the first or second line treatment of postmenopausal women with hormone-sensitive HER-2 negative metastatic breast cancer (MBC), but its activity in later lines is unknown. In Belgium, a compassionate Use Program (CUP) was temporarily established to provide palbociclib after at least 4 lines of systemic treatment for MBC. The UZ Leuven Multidisciplinary Breast Center included 82 patients in this CUP from September 28th 2015 to March 14th 2017. This analysis describes retrospectively collected efficacy (Revised RECIST guideline, version 1.1) and safety data from 68 patients with at least 6 months follow-up at the data cut-off point. The primary endpoint was clinical benefit, defined as being on treatment for at least 6 months (CR + PR + SD). Most of the patients (89.7%) used palbociclib in combination with letrozole. Other combinations are with tamoxifen (2.9%), fulvestrant (2.9%), exemestane (1.5%), anastrazole (1.5%) and megestrol (1.5%). At the data cut-off point, 18 patients are still on-treatment with palbociclib. The average duration of treatment is 5.7 months [range 2m- 17m]. The mean age of the patients was 66.3 years [range 34.8y – 85.9y] at the time of inclusion. Patients had had an average of 5.7 lines of systemic therapy [range 4 – 11 lines] before starting palbociclib, which was in 61.8% at least one line of chemotherapy. In this highly pretreated setting, 29 patients experienced stable disease lasting ≥ 6 months, resulting in an overall clinical benefit rate of 42.6%. 19.1% (13/68) showed stable disease for ≥ 9 months and 8% for ≥ 12 months. The subjective tolerance of the combination treatment was good, with 38% (26/68) of the patients discontinuing or delaying treatment following adverse events which were in the vast majority hematologic but asymptomatic. No factors predicting clinical benefit could be identified: use of chemotherapy before starting Palbociclib (p = 0.4644), age (p = 0.7029), time between primary breast cancer diagnosis and starting palbociclib (p = 0.1919) or time between first metastasis and starting palbociclib (p = 0.1108) and bone-only disease (p = 1,0000) were not significantly associated with clinical benefit at 6 months. These data not only support the findings of the PALOMA studies, but also show unexpectedly high clinical benefit and safety of palbociclib in heavily pretreated endocrine-resistant hormone receptor positive HER-2 negative advanced breast cancer. An update of these data will be presented. Citation Format: Hoste G, Punie K, Wildiers H, Neven P, Berteloot P, Van Nieuwenhuysen E, Han S, Concin N, Salihi R, Lefever I, Vergote I. Palbociclib in highly pretreated metastatic ER-positive HER-2 negative breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-22.

Abstract OT1-06-01: OPTIMA: A prospective randomized trial to validate the predictive utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in early breast cancer

Abstract Background: Multi-parameter gene expression assays (MPAs) are widely used to estimate individual patient residual risk in hormone-sensitive HER2-negative node-negative early breast cancer, allowing patients with low risk to safely avoid chemotherapy. Evidence for MPA use in node-positive breast cancer is limited. OPTIMA (Optimal Personalised Treatment of early breast cancer usIng Multi-parameter Analysis) aims to validate MPA's as predictors of chemotherapy sensitivity in a largely node-positive breast cancer population. Methods: OPTIMA is a partially blinded multi-center, phase 3 randomized controlled trial with an adaptive two-stage design. The main eligibility criteria are women or men aged 40 or older with resected ER-positive, HER2-negative breast cancer and up to 9 involved axillary lymph nodes. Randomization is to standard management (chemotherapy and endocrine therapy) or to MPA-directed treatment. Those with a “high risk” tumor MPA score receive standard management whilst those at “low risk” are treated with endocrine therapy alone. The preliminary phase (OPTIMA prelim) evaluated the performance of several MPAs to select a test to be used in the main efficacy trial based on economic analysis, and assessed the feasibility and acceptability of a large UK trial. OPTIMA prelim used Oncotype DX as the primary discriminator; the main trial will use Prosigna (PAM50) with Prosigna Score ≤60 defined as “low-risk”. The co-primary outcomes are (1) Invasive Disease Free Survival (IDFS) and (2) cost-effectiveness of test-directed therapy. Secondary outcomes include IDFS in “low-risk” patients, quality of life and additional survival measures. An integrated qualitative recruitment study will identify and address challenges to recruitment and informed consent. Tumor blocks from all consenting participants will be banked allowing the performance of alternative MPA technologies to be evaluated. Recruitment of 4500 patients will permit demonstration of 3% non-inferiority of test-directed treatment, with 5% significance and 85% power, assuming 3 years follow-up and a control arm 5-year IDFS of at least 85%. The addition of patients from OPTIMA prelim will allow non-inferiority to be assessed with 2.5% significance. Results: OPTIMA-prelim recruited 412 patients in 23 months from 35 sites with a 47% acceptance rate. The main study opened in January 2017. Early progress indicates that the recruitment target is achievable in the intended 46-month timescale through the participation of >100 sites Conclusion: OPTIMA, as one of two large scale prospective trials validating the use of test-guided chemotherapy decisions in node-positive early breast cancer, is expected to have a global impact on breast cancer treatment. Experience from OPTIMA prelim showed that patient advocate support and close engagement with sites will aid trial success. Funding: The project is funded in the UK by the NIHR HTA Programme (10/34/501). Views expressed are those of the authors and not those of the HTA Programme, NIHR, NHS or the DoH. Citation Format: Stein RC, Makris A, Hughes-Davies L, Macpherson IR, Hall PS, Cameron DA, Earl HM, Pinder SE, Poole CJ, Rea DW, McIntosh S, Harmer V, Morgan A, Rooshenas L, Conefrey C, Donovan JL, Hulme C, McCabe C, Stallard N, Campbell A, Higgins H, Bartlett JMS, Marshall A, Dunn JA. OPTIMA: A prospective randomized trial to validate the predictive utility and cost-effectiveness of gene expression test-directed chemotherapy decisions in early breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT1-06-01.

Surgical Oophorectomy is Ineffective Therapy in Women with Hormone-Receptor Positive Breast Cancer Who are in Historical, but Low-Progesterone Luteal Phase

The hormonal biology of the menstrual cycle has major relevance in the treatment of hormone-sensitive breast cancer. There are 500,000 new cases of hormone-receptor positive breast cancer in premenopausal women annually; 80% of these are among women in low- and middle-income countries. Surgical oophorectomy should play a major role in the treatment of these women. New data from two phase III clinical trials show that women who are in historical luteal phase, but have low progesterone levels at the times of their oophorectomy surgeries benefit little from this intervention. The unique sequence of hormonal signaling to micro-metastases which occurs in this situation offers a logical explanation for this observation. Because surgical oophorectomy is a safe and widely practical and affordable intervention, this new observation and explanation deserves the attention of the practicing global surgical community. Universal application of surgical oophorectomy treatment could save 100,000 lives of young women with breast cancer each year.

Growth of human breast cancers in Peromyscus.

ABSTRACTModeling breast cancer in general and hormone-sensitive breast cancer, in particular in mice, has several limitations. These are related to the inbred nature of laboratory mice, and do not allow adequate appreciation of the contribution of the host's genetic heterogeneity in tumor growth. In addition, the naturally low estrogen levels of mice makes estradiol supplementation obligatory for tumor growth. Here, we show that Peromyscus californicus, following cyclosporine-mediated immunosuppression, supports the growth of both MDA-MB-231 estrogen-independent and MCF7 estrogen receptor-positive breast cancers without exogenous estradiol supplementation. Tumor growth was inhibited by fulvestrant or letrozole, confirming that MCF7 xenografts remain hormone dependent in vivo and suggesting that P. californicus can be used as an alternative to conventional mice for the study of hormone-sensitive breast cancer. The fact that Peromyscus stocks are outbred also facilitates the study of breast cancer in genetically heterogenous populations.

The utility of anti-Müllerian hormone in the diagnosis and prediction of loss of ovarian function following chemotherapy for early breast cancer

AimChemotherapy results in permanent loss of ovarian function in some premenopausal women. Accurate identification in women with hormone-sensitive early breast cancer (eBC) would allow optimisation of subsequent endocrine treatment. We sought to assess whether analysis of anti-Müllerian hormone (AMH) using a sensitive automated assay could identify women who would not regain ovarian function after chemotherapy. MethodsData from women in the Ovarian Protection Trial in Premenopausal Breast Cancer Patients (OPTION) trial of goserelin (a gonadotrophin-releasing hormone (GnRH) analogue) for ovarian protection were analysed. Women were assessed for premature ovarian insufficiency (POI: amenorrhoea with elevated follicle-stimulating hormone (FSH)) at 24 months after diagnosis. The accuracy of AMH for the diagnosis of POI and its prediction from measurement at the end of chemotherapy was calculated. ResultsAMH below the level of detection showed good diagnostic accuracy for POI at 24 months (n = 73) with receiver operating characteristic (ROC) area under the curve of 0.86, sensitivity 1.0 and specificity 0.73 at the assay limit of detection. In women aged >40 at diagnosis who did not receive goserelin, AMH measured at end of chemotherapy also gave good prediction of POI at 24 months (area under the curve (AUC) 0.89 95% CI 0.75–1.0, n = 32), with sensitivity 0.91, specificity 0.82, diagnostic odds ratio (DOR) 42.8. FSH gave slightly lower AUC, and specificity was low at 0.55. Age but not tamoxifen impacted on AMH levels. ConclusionUsing this sensitive AMH assay, the finding of an undetectable AMH level in women aged >40 at the end of chemotherapy for eBC gave a good prediction that ovarian function would not return. This may allow alterations in post-chemotherapy endocrine management.

Abemaciclib Improves Outcome in Endocrine-Sensitive Breast Cancer

Abemaciclib Improves Outcome in Endocrine-Sensitive Breast Cancer

Endocrine Treatment of Breast Cancer: Current Perspectives, Future Directions

Breast cancer remains one of the major causes of death in women, and endocrine treatment is currently one of the mainstay of treatment in patients with estrogen receptor positive breast cancer. Endocrine therapy either slows down or stops the growth of hormone-sensitive tumors by blocking the body’s capability to yield hormones or by interfering with hormone action. In this paper, we intended to review various approaches of endocrine treatments for breast cancer highlighting successes and limitations. There are three settings where endocrine treatment of breast cancer can be used: neoadjuvant, adjuvant, or metastatic. Several strategies have also been developed to treat hormone-sensitive breast cancer which include ovarian ablation, blocking estrogen production, and stopping estrogen effects. Selective estrogen-receptor modulators (SERMs) (e.g. tamoxifen and raloxifene), aromatase inhibitors (AIs) (e.g. anastrozole, letrozole and exemestane), gonadotropin-releasing hormone agonists (GnRH) (e.g. goserelin), and selective estrogen receptor downregulators (SERDs) (e.g. fulvestrant) are currently used drugs to treat breast cancer. Tamoxifen is probably the first targeted therapy widely used in breast cancer treatment which is considered to be very effective as first line endocrine treatment in previously untreated patients and also can be used after other endocrine therapy and chemotherapy. AIs inhibit the action of enzyme aromatase which ultimately decrease the production of estrogen to stimulate the growth of ER+ breast cancer cells. GnRH agonists suppress ovarian function, inducing artificial menopause in premenopausal women. Endocrine treatments are cheap, well-tolerated and have a fixed single daily dose for all ages, heights and weights of patients. Endocrine treatments are not nearly as toxic as chemotherapy and frequent hospitalization can be avoided. New drugs in preliminary trials demonstrated the potential for improvement of the efficacy of endocrine therapy including overcoming resistance. However, the overall goals for breast cancer including endocrine therapy should focus on effective control of cancer, design personalized medical therapeutic approach, increase survival time and quality of life, and improve supportive and palliative care for end-stage disease.