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International Journal of Molecular... Sep 2020The introduction of CDK4/6 inhibitors in combination with endocrine therapy (ET) represents the most relevant advance in the management of hormone receptor (HR)... (Meta-Analysis)
Meta-Analysis
The introduction of CDK4/6 inhibitors in combination with endocrine therapy (ET) represents the most relevant advance in the management of hormone receptor (HR) positive, HER2-negative metastatic breast cancer over the last few years. This meta-analysis of randomized controlled trials (RCTs) is aimed to better characterize the efficacy of CDK4/6 inhibitors in some relevant subgroups and to test heterogeneity between different compounds with a particular focus on their ability to improve overall survival (OS). Pooled estimates of hazard ratios (HRs) were computed for progression-free survival (PFS), OS, and objective response rate (ORR) analysis in predefined subgroups to better understand treatment effect concerning specific patients' characteristics. To estimate the absolute benefit in terms of PFS, pooled survival curves were generated by pooling the data of all trials. A total of eight RCTs were included. Adding a CDK4/6 inhibitor to ET is beneficial in terms of PFS, irrespective of the presence or not of visceral metastases, the number of metastatic sites, and the length of the treatment-free interval (TFI). The addition of CDK4/6 inhibitors produces a significant OS improvement, both in aromatase inhibitor (AI)-sensitive (HR 0.75, 95% CI) and AI-resistant patients (HR 0.77, 95% CI [0.67-0.89]). Pooled data from each single drug show that palbociclib remains the only class member not showing a statistically significant HR for OS (HR 0.83, 95% CI [0.68-1.02]).
Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Humans; Neoplasm Metastasis; Prognosis; Protein Kinase Inhibitors; Survival Rate
PubMed: 32899139
DOI: 10.3390/ijms21176400 -
ESMO Open Aug 2020Several endocrine therapy (ET)-based treatments are available for patients with advanced breast cancer. We assessed the efficacy of different ET-based treatments in... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Several endocrine therapy (ET)-based treatments are available for patients with advanced breast cancer. We assessed the efficacy of different ET-based treatments in patients with hormone receptor-positive/HER2-negative advanced breast cancer with endocrine-sensitive or endocrine-resistant disease.
METHODS
We searched Medline and Cochrane Central Register of Controlled Trials up to 15 October 2019 and abstracts from major conferences from 2016 to October 2019. We included phase II/III randomised trials, comparing ≥2 ET-based treatments. Progression-free survival (PFS) and overall survival (OS) were analysed by network meta-analyses using MTC Bayesian models based on both fixed-effect and random-effect models; relative treatment effects were measured as HRs and 95% credibility intervals (CrI). All statistical tests were two-sided. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed and this systematic review is registered in the PROSPERO database.
RESULTS
55 publications reporting on 32 trials (n=12 293 patients) were included. Regarding PFS in the endocrine sensitive setting (n=5200; 12 trials), the combination of cyclin-dependent kinases (CDK)4/6-inhibitors (CDK4/6i)+fulvestrant 500 mg (F500) was likely the most effective treatment (surface under the cumulative ranking curve (SUCRA)=97.3%), followed by CDK4/6i+aromatase inhibitor ±goserelin; there was no significant difference between them (HR 0.82; 95% CrI 0.54-1.25). Regarding OS (n=2157; five trials), the most effective treatment was probably CDK4/6i+F500 (SUCRA=97.3%); comparing CDK4/6i+F500 versus F500 held a HR of 0.77 (95% CrI 0.63-0.95). Regarding PFS in the endocrine-resistant setting (n=6635; 20 trials), CDK4/6i+F500 was likely the most effective treatment (SUCRA=95.7%), followed by capivasertib+F500, without significant difference between them (HR 0.91; 95% CrI 0.60-1.36). For OS (n=4377; 11 trials), the most effective treatments were capivasertib+F500 (SUCRA=84.7%) and CDK4/6i+F500 (SUCRA=69.9%). Comparing CDK4/6i+F500 versus F500 held a HR of 0.77 (95% CrI 0.67-0.89).
CONCLUSIONS
CDK4/6i+F500 is likely the best treatment option in both endocrine-sensitive and endocrine-resistant diseases for PFS, and in endocrine-sensitive patients for OS. Concerning OS in endocrine-resistant patients, capivasertib+F500 and CDK4/6i+F500 are likely the best treatments.
PROSPERO REGISTRATION NUMBER
CRD42018104628.
Topics: Bayes Theorem; Breast Neoplasms; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Female; Fulvestrant; Humans; Network Meta-Analysis; Receptor, ErbB-2; Receptors, Estrogen
PubMed: 32847835
DOI: 10.1136/esmoopen-2020-000842 -
Medicine Jul 2020With the medical advancement some studies put forward that letrozole (LE), a specific aromatase inhibitor with the function of reducing oestrogen synthesis, has recently... (Comparative Study)
Comparative Study Meta-Analysis
Comparison of clomiphene and letrozole for superovulation in patients with unexplained infertility undergoing intrauterine insemination: A systematic review and meta-analysis.
BACKGROUND
With the medical advancement some studies put forward that letrozole (LE), a specific aromatase inhibitor with the function of reducing oestrogen synthesis, has recently been applied as a potentially better alternative compared with clomiphene citrate (CC), owing to that it has a superior efficacy as compared with CC in patients of unexplained infertility undergoing intrauterine insemination (IUI). However, there is no one study can clear and definite whether LE can replace the CC as first line drug.
OBJECTIVE
Our objective is to compare the LE with CC in the induction of ovulation in patients with unexplained infertility IUI.
METHOD
Searching databases consist of all kinds of searching tools, such as Medline, The Cochrane Library, Embase, PubMed, etc. All the include studies should meet our demand of this meta-analysis: RESULT:: Based on the current meta-analysis, we rigorously consider that LE has a likelihood to improve dominant follicles (MD= -0.56, I= 100%, P= .04; MD= -0.39, I= 73%, P = .0003, respectively) and reduces the miscarriage rate (RR= 0.61, I= 0%, P = .03). There is no significant differences between the 2 groups in The total rate of pregnancy, pregnancy rate per cycle, multiple pregnancy and endometrial thickness. (RR= 1.06, I= 11%, P = .38; RR= 1.09, I= 7%, P = .32; RR= 0.79, I= 0%, P = .46; respectively) CONCLUSION:: Combined with the results of current systematic review and meta-analysis through subgroup analysis and sensitivity analysis, we can be cautious: in general, compared with CC, LE is an effective treatment in the IUI cycle, has a likelihood to improve dominant follicles and reduces the miscarriage rate.
Topics: Clomiphene; Female; Fertility Agents, Female; Humans; Infertility, Female; Insemination, Artificial; Letrozole; Superovulation
PubMed: 32756085
DOI: 10.1097/MD.0000000000021006 -
Annals of Palliative Medicine Jul 2020In the NCCN guidelines version 1.2019, aromatase inhibitors (AIs) or tamoxifen (TAM) for 5 years plus ovarian function suppression (OFS) were recommended for... (Meta-Analysis)
Meta-Analysis
Aromatase inhibitors plus ovarian function suppression versus tamoxifen plus ovarian function suppression for premenopausal women with early stage breast cancer: a systematic review and meta-analysis.
In the NCCN guidelines version 1.2019, aromatase inhibitors (AIs) or tamoxifen (TAM) for 5 years plus ovarian function suppression (OFS) were recommended for premenopausal breast cancer patient who has higher risk of recurrence. The meta-analysis established a comparison of the curative effect of two adjuvant endocrine therapies. In order to obtain randomized controlled trials (RCTs) related to this metaanalysis, PubMed and Embase database were searched systematically in English during May 2019. Two reviewers screened the articles and extracted data based on the criteria recommended by the Cochrane collaboration for evaluating evidence in RCTs. The first outcome was disease-free survival (DFS). Overall survival (OS) was the other endpoint. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled utilizing fixed-effect model. The heterogeneity of this study has been described by Cochran's Q and the I2 statistics. Three RCTs which involved 7,203 premenopausal women with breast cancer were available in this meta-analysis. Pooled HRs showed that there was not difference between AIs plus OFS and TAM plus OFS in DFS (HR =0.87, 95% CI: 0.66-1.14, P=0.30). No statistical differences were found in OS between the two adjuvant therapies (HR =1.22, 95% CI: 0.75-1.99, P=0.43). Based on the included studies, there were no statistical differences between AIs plus OFS and TAM plus OFS in DFS and OS.
Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Humans; Tamoxifen
PubMed: 32434371
DOI: 10.21037/apm-20-488A -
Human Reproduction Update Jun 2020Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis.
BACKGROUND
Despite intense research, it remains intriguing why hormonal therapies in general and progestins in particular sometimes fail in endometriosis.
OBJECTIVE AND RATIONALE
We review here the action mechanisms of progesterone receptor ligands in endometriosis, identify critical differences between the effects of progestins on normal endometrium and endometriosis and envisage pathways to escape drug resistance and improve the therapeutic response of endometriotic lesions to such treatments.
SEARCH METHODS
We performed a systematic Pubmed search covering articles published since 1958 about the use of progestins, estro-progestins and selective progesterone receptor modulators, to treat endometriosis and its related symptoms. Two reviewers screened the titles and abstracts to select articles for full-text assessment.
OUTCOMES
Progesterone receptor signalling leads to down-regulation of estrogen receptors and restrains local estradiol production through interference with aromatase and 17 beta-hydroxysteroid dehydrogenase type 1. Progestins inhibit cell proliferation, inflammation, neovascularisation and neurogenesis in endometriosis. However, progesterone receptor expression is reduced and disrupted in endometriotic lesions, with predominance of the less active isoform (PRA) over the full-length, active isoform (PRB), due to epigenetic abnormalities affecting the PGR gene transcription. Oxidative stress is another mechanism involved in progesterone resistance in endometriosis. Among the molecular targets of progesterone in the normal endometrium that resist progestin action in endometriotic cells are the nuclear transcription factor FOXO1, matrix metalloproteinases, the transmembrane gap junction protein connexin 43 and paracrine regulators of estradiol metabolism. Compared to other phenotypes, deep endometriosis appears to be more resistant to size regression upon medical treatments. Individual genetic characteristics can affect the bioavailability and pharmacodynamics of hormonal drugs used to treat endometriosis and, hence, explain part of the variability in the therapeutic response.
WIDER IMPLICATIONS
Medical treatment of endometriosis needs urgent innovation, which should start by deeper understanding of the disease core features and diverse phenotypes and idiosyncrasies, while moving from pure hormonal treatments to drug combinations or novel molecules capable of restoring the various homeostatic mechanisms disrupted by endometriotic lesions.
Topics: Endometriosis; Endometrium; Female; Fertility Agents, Female; Humans; Ligands; Peritoneal Diseases; Progesterone; Progestins; Receptors, Progesterone; Treatment Outcome; Uterine Diseases
PubMed: 32412587
DOI: 10.1093/humupd/dmaa009 -
Frontiers in Nutrition 2020Interactions are occurring in the course of liberation, absorption, distribution, metabolism, and excretion of active ingredients, or at the target receptors. They are...
Interactions are occurring in the course of liberation, absorption, distribution, metabolism, and excretion of active ingredients, or at the target receptors. They are causing therapy failures and undesirable events. Forty-seven of fifty-seven human hepatic isoenzymes are specific and relevant in hormone and vitamin metabolism and biosynthesis. Aromatase (syn. CYP19A1) is one of the specific CYP450 isoenzymes so far not elucidated in detail. As aromatase-inhibiting phytochemicals are currently recommended for breast cancer prevention and as add-on accompanying aromatase-inhibitor pharmacotherapy, it was the aim of this literature review to assess whether a common interpretation on genetic and -omics basis could be found. Articles retrieved showed that traditional antioxidation diet is one of the most approved explanations of inhibition of aromatase by phytonutrients of flavonoid derivatives. Flavonoids compete for the oxygen provided by the heme moiety of aromatase in the course of aromatase-catalyzed conversion of steroid precursors to estrogens. Flavonoids are therefore promoted for breast cancer prevention. A further explanation of flavonoids' mechanism of action proposed was related to enzymatic histone deacetylation. By keeping DNA-structure wide through a high acetylation degree, acetylated histones favor transcription and replication. This mechanism corresponds to a procedure of switching genes on. Inhibiting acetylation and therefore switching genes off might be an important regulation of repressing cancer genes. Aromatase expression depends on the genotype and phenotype of a person. Aromatase itself depends on the expression of the heme moiety encoded in the genotype. Biosynthesis of porphyrins in turn depends on the substrates succinate and glycine, as well as on a series of further enzymes, with ALA synthetase as the rate-limiting step. The effect of the heme moiety as prosthetic group of aromatase further depends on the absorption of iron as a function of pH and redox state. To assess the function of aromatase precisely, multiple underlying biochemical pathways need to be evaluated. As a conclusion, the genetic regulation of metabolism is a complex procedure affecting multiple pathways. To understand a metabolic step, multiple underlying individually performing reactions need to be considered if personalized (nutritional) medicine should bring an advantage for a patient. Nutrition sciences need to consider the genome of an individual to truly find answers to nutrition-derived non-communicable diseases. With current GWAS (genome-wide association study) approaches, inherited errors of metabolism are identified and ideally treated effectively. It is much more difficult to get a precise genetic profile for non-communicable diseases stemming from multifactorial causes. Polygenic risks evaluation is feasible but diagnostic tools are not yet available in a desired extent. Neither flavonoid researchers nor providers of genetic testing kits are going into the details needed for a truly personalized nutritional medicine. The next step with profiling the exome and then the whole genome is on the threshold of becoming routine diagnosis and of bringing the desired details.
PubMed: 32328497
DOI: 10.3389/fnut.2020.00037 -
Heliyon Mar 2020The cytochrome P450 enzyme functions as the rate-limiting enzyme in changing androgens to estrogens. Inhibition of aromatase is one of the significant objectives of... (Review)
Review
The cytochrome P450 enzyme functions as the rate-limiting enzyme in changing androgens to estrogens. Inhibition of aromatase is one of the significant objectives of treatment of hormone-dependent diseases such as breast cancer, especially in post-menopausal women. Natural compounds like chrysin, as a flavor that has a high concentration in honey and propolis, are rich sources of them can be useful in inhibiting aromatase for chemoprevention following treatment or in women at risk of acquiring breast cancer. This study intended to summarize the existing evidence on the effect of chrysin on aromatase activity. We systematically searched Science Direct, PubMed and Google Scholar and hand searched the reference lists of identified relevant articles, up to 5 February, 2019. Articles with English abstracts that reported the effect of chrysin on aromatase inhibition and without publication date restriction were investigated. Twenty relevant articles were chosen from a total of 1721 articles. Only one study was performed on humans and two studies were assayed on rats, while other studies were evaluated in vitro. All the studies except one showed that chrysin had the potency of aromatase inhibition; however, only one study performed on endometrial stromal cells showed that chrysin and naringenin did not indicate aromatase inhibitory properties. Various assay methods and experimental conditions were the important aspects leading to different results between the studies. Chrysin has potency in inhibition of the aromatase enzyme and thus can be useful in preventing and treating the hormone-dependent breast cancer and as an adjuvant therapy for estrogen-dependent diseases.
PubMed: 32181408
DOI: 10.1016/j.heliyon.2020.e03557 -
The Cochrane Database of Systematic... Mar 2020Approximately 80% of breast cancers amongst premenopausal women are hormone receptor-positive. Adjuvant endocrine therapy is an integral component of care for hormone... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Approximately 80% of breast cancers amongst premenopausal women are hormone receptor-positive. Adjuvant endocrine therapy is an integral component of care for hormone receptor-positive breast cancer and in premenopausal women includes oestrogen receptor blockade with tamoxifen, temporary suppression of ovarian oestrogen synthesis by luteinising hormone releasing hormone (LHRH) agonists, and permanent interruption of ovarian oestrogen synthesis with oophorectomy or radiotherapy. Recent international consensus statements recommend single-agent tamoxifen or aromatase inhibitors with ovarian function suppression (OFS) as the current standard adjuvant endocrine therapy for premenopausal women (often preceded by chemotherapy). This review examined the role of adding OFS to another treatment (i.e. chemotherapy, endocrine therapy, or both) or comparing OFS to no further adjuvant treatment.
OBJECTIVES
To assess effects of OFS for treatment of premenopausal women with hormone receptor-positive early breast cancer.
SEARCH METHODS
For this review update, we searched the Specialised Register of the Cochrane Breast Cancer Group, MEDLINE, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL; 2019, Issue 8), the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP), and ClinicalTrials.gov on 26 September 2019. We screened the reference lists of related articles, contacted trial authors, and applied no language restrictions.
SELECTION CRITERIA
We included all randomised trials assessing any method of OFS, that is, oophorectomy, radiation-induced ovarian ablation, or LHRH agonists, as adjuvant treatment for premenopausal women with early-stage breast cancer. We included studies that compared (1) OFS versus observation, (2) OFS + chemotherapy versus chemotherapy, (3) OFS + tamoxifen versus tamoxifen, and (4) OFS + chemotherapy + tamoxifen versus chemotherapy + tamoxifen.
DATA COLLECTION AND ANALYSIS
Two review authors independently extracted data and assessed risk of bias and certainty of evidence using the GRADE approach. Hazard ratios (HRs) were derived for time-to-event outcomes, and meta-analysis was performed using a fixed-effect model. The primary outcome measures were overall survival (OS) and disease-free survival (DFS). Toxicity, contralateral breast cancer, and second malignancy were represented as risk ratios (RRs), and quality of life data were extracted when provided.
MAIN RESULTS
This review update included 15 studies involving 11,538 premenopausal women with hormone receptor-positive early breast cancer; these studies were conducted from 1978 to 2014. Some of these treatments are not current standard of care, and early studies did not assess HER2 receptor status. Studies tested OFS versus observation (one study), OFS plus chemotherapy versus chemotherapy (six studies), OFS plus tamoxifen versus tamoxifen (six studies), and OFS plus chemotherapy and tamoxifen versus chemotherapy and tamoxifen (two studies). Of those studies that reported the chemotherapy regimen, an estimated 72% of women received an anthracycline. The results described below relate to the overall comparison of OFS versus no OFS. High-certainty evidence shows that adding OFS to treatment resulted in a reduction in mortality (hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.78 to 0.94; 11 studies; 10,374 women; 1933 reported events). This treatment effect was seen when OFS was added to observation, to tamoxifen, or to chemotherapy and tamoxifen. The effect on mortality was not observed when OFS was added to chemotherapy without tamoxifen therapy (HR 0.95, 95% CI 0.82 to 1.09; 5 studies; 3087 women; median follow-up: range 7.7 to 12.1 years). The addition of OFS resulted in improved DFS (HR 0.83, 95% CI 0.77 to 0.90; 10 studies; 8899 women; 2757 reported events; high-certainty evidence). The DFS treatment effect persisted when OFS was added to observation, to tamoxifen, and to chemotherapy and tamoxifen. The effect on DFS was reduced when OFS was added to chemotherapy without tamoxifen therapy (HR 0.90, 95% CI 0.79 to 1.01; 5 studies; 2450 women). Heterogeneity was low to moderate across studies for DFS and OS (respectively). Evidence suggests that adding OFS slightly increases the incidence of hot flushes (grade 3/4 or any grade; risk ratio (RR) 1.60, 95% CI 1.41 to 1.82; 6 studies; 5581 women; low-certainty evidence, as this may have been under-reported in these studies). Two other studies that could not be included in the meta-analysis reported a higher number of hot flushes in the OFS group than in the no-OFS group. Seven studies involving 5354 women collected information related to mood; however this information was reported as grade 3 or 4 depression, anxiety, or neuropsychiatric symptoms, or symptoms were reported without the grade. Two studies reported an increase in depression, anxiety, and neuropsychiatric symptoms in the OFS group compared to the no-OFS group, and five studies indicated an increase in anxiety in both treatment groups (but no difference between groups) or no difference overall in symptoms over time or between treatment groups. A single study reported bone health as osteoporosis (defined as T score < -2.5); this limited evidence suggests that OFS increases the risk of osteoporosis compared to no-OFS at median follow-up of 5.6 years (RR 1.16, 95% CI 1.10 to 28.82; 2011 women; low-certainty evidence). Adding OFS to treatment likely reduces the risk of contralateral breast cancer (HR 0.75, 95% CI 0.57 to 0.97; 9 studies; 9138 women; moderate-certainty evidence). Quality of life was assessed in five studies; four studies used validated tools, and the fifth study provided no information on how data were collected. Two studies reported worse quality of life indicators (i.e. vaginal dryness, day and night sweats) for women receiving OFS compared to those in the no-OFS group. The other two studies indicated worsening of symptoms (e.g. vasomotor, gynaecological, vaginal dryness, decline in sexual interest, bone and joint pain, weight gain); however these side effects were reported in both OFS and no-OFS groups. The study that did not use a validated quality of life tool described no considerable differences between groups.
AUTHORS' CONCLUSIONS
This review found evidence that supports adding OFS for premenopausal women with early, hormone receptor-positive breast cancers. The benefit of OFS persisted when compared to observation, and when added to endocrine therapy (tamoxifen) or chemotherapy and endocrine therapy (tamoxifen). The decision to use OFS may depend on the overall risk assessment based on tumour and patient characteristics, and may follow consideration of all side effects that occur with the addition of OFS.
Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Chemotherapy, Adjuvant; Female; Gonadotropin-Releasing Hormone; Humans; Premenopause; Randomized Controlled Trials as Topic; Survival Analysis; Tamoxifen; Treatment Outcome
PubMed: 32141074
DOI: 10.1002/14651858.CD013538 -
Journal of Medical Genetics Sep 2020Endometrial cancer is one of the most commonly diagnosed cancers in women. Although there is a hereditary component to endometrial cancer, most cases are thought to be...
INTRODUCTION
Endometrial cancer is one of the most commonly diagnosed cancers in women. Although there is a hereditary component to endometrial cancer, most cases are thought to be sporadic and lifestyle related. The aim of this study was to systematically review prospective and retrospective case-control studies, meta-analyses and genome-wide association studies to identify genomic variants that may be associated with endometrial cancer risk.
METHODS
We searched MEDLINE, Embase and CINAHL from 2007 to 2019 without restrictions. We followed PRISMA 2009 guidelines. The search yielded 3015 hits in total. Following duplicate exclusion, 2674 abstracts were screened and 453 full-texts evaluated based on our pre-defined screening criteria. 149 articles were eligible for inclusion.
RESULTS
We found that single nucleotide polymorphisms (SNPs) in , , , , and were strongly associated with incident endometrial cancer. Nineteen variants were reported with genome-wide significance and a further five with suggestive significance. No convincing evidence was found for the widely studied variant rs2279744. Publication bias and false discovery rates were noted throughout the literature.
CONCLUSION
Endometrial cancer risk may be influenced by SNPs in genes involved in cell survival, oestrogen metabolism and transcriptional control. Larger cohorts are needed to identify more variants with genome-wide significance.
Topics: Aromatase; Endometrial Neoplasms; Female; Genetic Predisposition to Disease; Genome-Wide Association Study; Hepatocyte Nuclear Factor 1-beta; Humans; Kruppel-Like Transcription Factors; Polymorphism, Single Nucleotide; Prospective Studies; Proto-Oncogene Proteins c-mdm2; Proto-Oncogene Proteins c-myc; Risk Factors; SOXC Transcription Factors; eIF-2 Kinase
PubMed: 32066633
DOI: 10.1136/jmedgenet-2019-106529 -
Breast Cancer (Tokyo, Japan) May 2020In establishing the 2018 Breast Cancer Practice Guidelines of the Japan Breast Cancer Society, we explored the optimal first-line endocrine therapy for advanced... (Meta-Analysis)
Meta-Analysis
BACKGROUND
In 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.
METHODS
We 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.
RESULTS
Four 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.
CONCLUSION
In 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.
Topics: Aromatase Inhibitors; Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Postmenopause; Prognosis; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone
PubMed: 32043218
DOI: 10.1007/s12282-020-01054-7