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Lancet (London, England) Jan 2020Two large clinical trials have shown a reduced rate of breast cancer development in high-risk women in the initial 5 years of follow-up after use of aromatase inhibitors... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Two large clinical trials have shown a reduced rate of breast cancer development in high-risk women in the initial 5 years of follow-up after use of aromatase inhibitors (MAP.3 and International Breast Cancer Intervention Study II [IBIS-II]). Here, we report blinded long-term follow-up results for the IBIS-II trial, which compared anastrozole with placebo, with the objective of determining the efficacy of anastrozole for preventing breast cancer (both invasive and ductal carcinoma in situ) in the post-treatment period.
METHODS
IBIS-II is an international, randomised, double-blind, placebo-controlled trial. Postmenopausal women at increased risk of developing breast cancer were recruited and were randomly assigned (1:1) to either anastrozole (1 mg per day, oral) or matching placebo daily for 5 years. After treatment completion, women were followed on a yearly basis to collect data on breast cancer incidence, death, other cancers, and major adverse events (cardiovascular events and fractures). The primary outcome was all breast cancer.
FINDINGS
3864 women were recruited between Feb 2, 2003, and Jan 31, 2012. 1920 women were randomly assigned to 5 years anastrozole and 1944 to placebo. After a median follow-up of 131 months (IQR 105-156), a 49% reduction in breast cancer was observed for anastrozole (85 vs 165 cases, hazard ratio [HR] 0·51, 95% CI 0·39-0·66, p<0·0001). The reduction was larger in the first 5 years (35 vs 89, 0·39, 0·27-0·58, p<0·0001), but still significant after 5 years (50 vs 76 new cases, 0·64, 0·45-0·91, p=0·014), and not significantly different from the first 5 years (p=0·087). Invasive oestrogen receptor-positive breast cancer was reduced by 54% (HR 0·46, 95% CI 0·33-0·65, p<0·0001), with a continued significant effect in the period after treatment. A 59% reduction in ductal carcinoma in situ was observed (0·41, 0·22-0·79, p=0·0081), especially in participants known to be oestrogen receptor-positive (0·22, 0·78-0·65, p<0·0001). No significant difference in deaths was observed overall (69 vs 70, HR 0·96, 95% CI 0·69-1·34, p=0·82) or for breast cancer (two anastrozole vs three placebo). A significant decrease in non-breast cancers was observed for anastrozole (147 vs 200, odds ratio 0·72, 95% CI 0·57-0·91, p=0·0042), owing primarily to non-melanoma skin cancer. No excess of fractures or cardiovascular disease was observed.
INTERPRETATION
This analysis has identified a significant continuing reduction in breast cancer with anastrozole in the post-treatment follow-up period, with no evidence of new late side-effects. Further follow-up is needed to assess the effect on breast cancer mortality.
FUNDING
Cancer Research UK, the National Health and Medical Research Council Australia, Breast Cancer Research Foundation, Sanofi Aventis, and AstraZeneca.
Topics: Administration, Oral; Adult; Aged; Anastrozole; Aromatase Inhibitors; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Female; Follow-Up Studies; Humans; Incidence; Middle Aged; Placebos; Treatment Outcome; United Kingdom
PubMed: 31839281
DOI: 10.1016/S0140-6736(19)32955-1 -
Clinical Cancer Research : An Official... Feb 2020neoMONARCH assessed the biological effects of abemaciclib in combination with anastrozole in the neoadjuvant setting. (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
neoMONARCH assessed the biological effects of abemaciclib in combination with anastrozole in the neoadjuvant setting.
PATIENTS AND METHODS
Postmenopausal women with stage I-IIIB HR/HER2 breast cancer were randomized to a 2-week lead-in of abemaciclib, anastrozole, or abemaciclib plus anastrozole followed by 14 weeks of the combination. The primary objective evaluated change in Ki67 from baseline to 2 weeks of treatment. Additional objectives included clinical, radiologic, and pathologic responses, safety, as well as gene expression changes related to cell proliferation and immune response.
RESULTS
Abemaciclib, alone or in combination with anastrozole, achieved a significant decrease in Ki67 expression and led to potent cell-cycle arrest after 2 weeks of treatment compared with anastrozole alone. More patients in the abemaciclib-containing arms versus anastrozole alone achieved complete cell-cycle arrest (58%/68% vs. 14%, < 0.001). At the end of treatment, following 2 weeks lead-in and 14 weeks of combination therapy, 46% of intent-to-treat patients achieved a radiologic response, with pathologic complete response observed in 4%. The most common all-grade adverse events were diarrhea (62%), constipation (44%), and nausea (42%). Abemaciclib, anastrozole, and the combination inhibited cell-cycle processes and estrogen signaling; however, combination therapy resulted in increased cytokine signaling and adaptive immune response indicative of enhanced antigen presentation and activated T-cell phenotypes.
CONCLUSIONS
Abemaciclib plus anastrozole demonstrated biological and clinical activity with generally manageable toxicities in patients with HR/HER2 early breast cancer. Abemaciclib led to potent cell-cycle arrest, and in combination with anastrozole, enhanced immune activation.
Topics: Adaptive Immunity; Adult; Aged; Aged, 80 and over; Aminopyridines; Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Cell Cycle Checkpoints; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Estrogen Receptor alpha; Female; Humans; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Patient Safety; Postmenopause; Receptor, ErbB-2; Receptors, Progesterone; Treatment Outcome
PubMed: 31615937
DOI: 10.1158/1078-0432.CCR-19-1425 -
The Cochrane Database of Systematic... May 2018Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Polycystic ovary syndrome (PCOS) is the most common cause of infrequent periods (oligomenorrhoea) and absence of periods (amenorrhoea). It affects about 4% to 8% of women worldwide and often leads to anovulatory subfertility. Aromatase inhibitors (AIs) are a class of drugs that were introduced for ovulation induction in 2001. Since about 2001 clinical trials have reached differing conclusions as to whether the AI letrozole is at least as effective as the first-line treatment clomiphene citrate (CC).
OBJECTIVES
To evaluate the effectiveness and safety of aromatase inhibitors for subfertile women with anovulatory PCOS for ovulation induction followed by timed intercourse or intrauterine insemination (IUI).
SEARCH METHODS
We searched the following sources from inception to November 2017 to identify relevant randomised controlled trials (RCTs): the Cochrane Gynaecology and Fertility Group Specialised Register, the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, Pubmed, LILACS, Web of Knowledge, the World Health Organization (WHO) clinical trials register and Clinicaltrials.gov. We also searched the references of relevant articles. We did not restrict the searches by language or publication status.
SELECTION CRITERIA
We included all RCTs of AIs used alone or with other medical therapies for ovulation induction in women of reproductive age with anovulatory PCOS.
DATA COLLECTION AND ANALYSIS
Two review authors independently selected trials, extracted the data and assessed risks of bias. We pooled studies where appropriate using a fixed-effect model to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for most outcomes, and risk differences (RDs) for ovarian hyperstimulation syndrome (OHSS). The primary outcomes were live birth and OHSS. Secondary outcomes were clinical pregnancy, miscarriage and multiple pregnancy. We assessed the quality of the evidence for each comparison using GRADE methods.
MAIN RESULTS
This is a substantive update of a previous review. We identified 16 additional studies for the 2018 update. We include 42 RCTs (7935 women). The aromatase inhibitor letrozole was used in all studies.Letrozole compared to clomiphene citrate (CC) with or without adjuncts followed by timed intercourseLive birth rates were higher with letrozole (with or without adjuncts) compared to clomiphene citrate (with our without adjuncts) followed by timed intercourse (OR 1.68, 95% CI 1.42 to 1.99; 2954 participants; 13 studies; I = 0%; number needed to treat for an additional beneficial outcome (NNTB) = 10; moderate-quality evidence). There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate (0.5% in both arms: risk difference (RD) -0.00, 95% CI -0.01 to 0.00; 2536 participants; 12 studies; I = 0%; high-quality evidence). There is evidence for a higher pregnancy rate in favour of letrozole (OR 1.56, 95% CI 1.37 to 1.78; 4629 participants; 25 studies; I = 1%; NNTB = 10; moderate-quality evidence). There is little or no difference between treatment groups in the rate of miscarriage by pregnancy (20% with CC versus 19% with letrozole; OR 0.94, 95% CI 0.70 to 1.26; 1210 participants; 18 studies; I = 0%; high-quality evidence) and multiple pregnancy rate (1.7% with CC versus 1.3% with letrozole; OR 0.69, 95% CI 0.41 to 1.16; 3579 participants; 17 studies; I = 0%; high-quality evidence). However, a funnel plot showed mild asymmetry, indicating that some studies in favour of clomiphene might be missing.Letrozole compared to laparoscopic ovarian drillingThere is low-quality evidence that live birth rates are similar with letrozole or laparoscopic ovarian drilling (OR 1.38, 95% CI 0.95 to 2.02; 548 participants; 3 studies; I = 23%; low-quality evidence). There is insufficient evidence for a difference in OHSS rates (RD 0.00, 95% CI -0.01 to 0.01; 260 participants; 1 study; low-quality evidence). There is low-quality evidence that pregnancy rates are similar (OR 1.28, 95% CI 0.94 to 1.74; 774 participants; 5 studies; I = 0%; moderate-quality evidence). There is insufficient evidence for a difference in miscarriage rate by pregnancy (OR 0.66, 95% CI 0.30 to 1.43; 240 participants; 5 studies; I = 0%; moderate-quality evidence), or multiple pregnancies (OR 3.00, 95% CI 0.12 to 74.90; 548 participants; 3 studies; I = 0%; low-quality evidence).Additional comparisons were made for Letrozole versus placebo, Selective oestrogen receptor modulators (SERMS) followed by intrauterine insemination (IUI), follicle stimulating hormone (FSH), Anastrozole, as well as dosage and administration protocols. There is insufficient evidence for a difference in either group of treatment due to a limited number of studies. Hence more research is necessary.
AUTHORS' CONCLUSIONS
Letrozole appears to improve live birth and pregnancy rates in subfertile women with anovulatory polycystic ovary syndrome, compared to clomiphene citrate. There is high-quality evidence that OHSS rates are similar with letrozole or clomiphene citrate. There is high-quality evidence of no difference in miscarriage rates or multiple pregnancy rates. There is low-quality evidence of no difference in live birth and pregnancy rates between letrozole and laparoscopic ovarian drilling, although there were few relevant studies. For the 2018 update, we added good-quality trials, upgrading the quality of the evidence.
Topics: Abortion, Spontaneous; Anastrozole; Aromatase Inhibitors; Birth Rate; Clomiphene; Coitus; Female; Fertility Agents, Female; Humans; Infertility, Female; Letrozole; Live Birth; Nitriles; Ovarian Hyperstimulation Syndrome; Ovary; Ovulation Induction; Polycystic Ovary Syndrome; Pregnancy; Pregnancy Outcome; Pregnancy, Multiple; Randomized Controlled Trials as Topic; Triazoles
PubMed: 29797697
DOI: 10.1002/14651858.CD010287.pub3 -
Journal of Clinical Oncology : Official... Apr 2017Purpose The purpose of this study was to examine outcomes associated with hormonal maintenance therapy (HMT) compared with routine observation (OBS) after primary... (Comparative Study)
Comparative Study
Purpose The purpose of this study was to examine outcomes associated with hormonal maintenance therapy (HMT) compared with routine observation (OBS) after primary cytoreductive surgery and platinum-based chemotherapy in women with stage II to IV low-grade serous carcinoma of the ovary or peritoneum. Patients and Methods Eligibility criteria for patients from our database were: treatment with primary surgery followed by platinum-based chemotherapy, stage II to IV disease, at least 2 years of follow-up for patients who had not experienced recurrence, and adequate clinical information. The two groups were compared for progression-free survival (PFS) and overall survival, and a multivariable Cox regression analysis was performed. Subset analyses for patients who were disease free or had persistent disease were also performed. Results Between 1981 and 2013, 203 eligible patients-133 who underwent OBS and 70 who received HMT-were seen at our institution. Median PFS for patients who underwent OBS was 26.4 months, compared with 64.9 months for those who received HMT ( P < .001). No statistically significant difference in overall survival was observed between the two groups (102.7 v 115.7 months, respectively). For subgroups of women who were disease free or had persistent disease, median PFS was superior for those who received HMT (81.1 v 30.0 months; P < .001 and 38.1 v 15.2 months; P < .001, respectively). Women who received HMT had a significantly lower risk of disease progression compared with those who underwent OBS (hazard ratio, 0.44; 95% CI, 0.31 to 0.64; P < .001). Conclusion Women with stage II to IV low-grade serous carcinoma who received HMT after primary treatment had significantly longer PFS compared with women who underwent OBS. These findings warrant further investigation using a prospective trial design.
Topics: Adult; Aged; Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Cytoreduction Surgical Procedures; Disease Progression; Disease-Free Survival; Female; Follow-Up Studies; Humans; Letrozole; Leuprolide; Maintenance Chemotherapy; Medroxyprogesterone Acetate; Middle Aged; Neoplasm Grading; Neoplasm Staging; Neoplasms, Cystic, Mucinous, and Serous; Nitriles; Ovarian Neoplasms; Peritoneal Neoplasms; Platinum Compounds; Survival Rate; Tamoxifen; Triazoles; Watchful Waiting; Young Adult
PubMed: 28221866
DOI: 10.1200/JCO.2016.71.0632 -
Journal of Neuroinflammation Jun 2020Research on the brain-gut-microbiota axis has led to accumulating interest in gut microbiota dysbiosis and intestinal barrier dysfunction in Alzheimer's disease (AD)....
BACKGROUND
Research on the brain-gut-microbiota axis has led to accumulating interest in gut microbiota dysbiosis and intestinal barrier dysfunction in Alzheimer's disease (AD). Our previous studies have demonstrated neurotoxic effects of 27-hydroxycholesterol (27-OHC) in in vitro and in vivo models. Here, alterations in the gut microbiota and intestinal barrier functions were investigated as the possible causes of cognitive deficits induced by 27-OHC treatment.
METHODS
Male APP/PS1 transgenic and C57BL/6J mice were treated for 3 weeks with 27-OHC (5.5 mg/kg/day, subcutaneous injection) and either a 27-OHC synthetase inhibitor (anastrozole, ANS) or saline. The Morris water maze and passive avoidance test were used to assess cognitive impairment. Injuries of the intestine were evaluated by histopathological examination. Intestinal barrier function was assessed by plasma diamine oxidase (DAO) activity and D-lactate. Systemic and intestinal inflammation were evaluated by IL-1β, TNF-α, IL-10, and IL-17 concentrations as determined by ELISA. The fecal microbiome and short-chain fatty acids (SCFAs) were analyzed using 16S rDNA sequencing and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Tight junction proteins were evaluated in the ileum and colon by qRT-PCR and Western blots. Tight junction ultrastructure was examined by transmission electron microscopy.
RESULTS
Treatment with 27-OHC resulted in severe pathologies in the ileum and colon. There was impaired intestinal barrier integrity as indicated by dilated tight junctions and downregulation of tight junction proteins, including occludin, claudin 1, claudin 5, and ZO-1, and signs of inflammation (increased IL-1β, TNF-α, and IL-17). Fecal 16S rDNA sequencing and taxonomic analysis further revealed a decreased abundance of Roseburia and reduced fecal levels of several SCFAs in 27-OHC-treated mice. Meanwhile, co-treatment with ANS reduced intestinal inflammation and partially preserved intestinal barrier integrity in the presence of 27-OHC.
CONCLUSIONS
The current study demonstrates for the first time that 27-OHC treatment aggravates AD-associated pathophysiological alterations, specifically gut microbiota dysbiosis and intestinal barrier dysfunction, which suggests that the gut microbiome and intestinal barrier function warrant further investigation as potential targets to mitigate the neurotoxic impact of 27-OHC on cognitive function and the development of AD.
Topics: Anastrozole; Animals; Aromatase Inhibitors; Avoidance Learning; Cognitive Dysfunction; Dysbiosis; Gastrointestinal Microbiome; Hydroxycholesterols; Intestinal Mucosa; Intestines; Male; Maze Learning; Mice; Mice, Transgenic; Tight Junction Proteins; Tight Junctions
PubMed: 32593306
DOI: 10.1186/s12974-020-01873-7 -
The Journal of Clinical Endocrinology... Dec 2016Growth of short children in puberty is limited by the effect of estrogen on epiphyseal fusion. (Randomized Controlled Trial)
Randomized Controlled Trial
CONTEXT
Growth of short children in puberty is limited by the effect of estrogen on epiphyseal fusion.
OBJECTIVES
To compare: 1) the efficacy and safety of aromatase inhibitors (AIs) vs GH vs AI/GH on increasing adult height potential in pubertal boys with severe idiopathic short stature (ISS); and 2) differences in body composition among groups.
DESIGN
Randomized three-arm open-label comparator.
SETTING
Outpatient clinical research.
PATIENTS
Seventy-six pubertal boys [mean (SE) age, 14.1 (0.1) years] with ISS [height SD score (SDS), -2.3 (0.0)].
INTERVENTION
Daily AIs (anastrozole or letrozole), GH, or AI/GH for 24-36 months.
OUTCOMES
Anthropometry, bone ages, dual x-ray absorptiometry, spine x-rays, hormones, safety labs.
RESULTS
Height gain [mean (SE)] at 24 months was: AI, +14.0 (0.8) cm; GH, +17.1 (0.9) cm; AI/GH, +18.9 (0.8) cm (P < .0006, analysis of covariance). Height SDS was: AI, -1.73 (0.12); GH, -1.43 (0.14); AI/GH, -1.25 (0.12) (P < .0012). Those treated through 36 months grew more. Regardless of treatment duration, height SDS at near-final height [n = 71; age, 17.4 (0.2) years; bone age, 15.3 (0.1) years; height achieved, ∼97.6%] was: AI, -1.4 (0.1); GH, -1.4 (0.2); AI/GH, -1.0 (0.1) (P = .06). Absolute height change was: AI, +18.2 (1.6) cm; GH, +20.6 (1.5) cm; AI/GH, +22.5 (1.4) cm (P = .01) (expected height gain at -2.0 height SDS, +13.0 cm). AI/GH had higher fat free mass accrual. Measures of bone health, safety labs, and adverse events were similar in all groups. Letrozole caused higher T and lower estradiol than anastrozole.
CONCLUSIONS
Combination therapy with AI/GH increases height potential in pubertal boys with ISS more than GH and AI alone treated for 24-36 months with a strong safety profile.
Topics: Adolescent; Anastrozole; Aromatase Inhibitors; Body Composition; Body Height; Drug Therapy, Combination; Dwarfism; Growth Hormone; Humans; Letrozole; Male; Nitriles; Outcome Assessment, Health Care; Puberty; Triazoles
PubMed: 27710241
DOI: 10.1210/jc.2016-2891 -
The Lancet. Oncology Sep 2023The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of... (Randomized Controlled Trial)
Randomized Controlled Trial
Neoadjuvant palbociclib plus either giredestrant or anastrozole in oestrogen receptor-positive, HER2-negative, early breast cancer (coopERA Breast Cancer): an open-label, randomised, controlled, phase 2 study.
BACKGROUND
The development of more potent selective oestrogen receptor antagonists and degraders (SERDs) that can be orally administered could help to address the limitations of current endocrine therapies. We report the primary and final analyses of the coopERA Breast Cancer study, designed to test whether giredestrant, a highly potent, non-steroidal, oral SERD, would show a stronger anti-proliferative effect than anastrozole after 2 weeks for oestrogen receptor-positive, HER2-negative, untreated early breast cancer.
METHODS
In this open-label, randomised, controlled, phase 2 study, postmenopausal women were eligible if they were aged 18 years or older; had clinical T stage (cT)1c to cT4a-c (≥1·5 cm within cT1c) oestrogen receptor-positive, HER2-negative, untreated early breast cancer; an Eastern Cooperative Oncology Group performance status of 0-1; and baseline Ki67 score of at least 5%. The study was conducted at 59 hospital or clinic sites in 11 countries globally. Participants were randomly assigned (1:1) to giredestrant 30 mg oral daily or anastrozole 1 mg oral daily on days 1-14 (window-of-opportunity phase) via an interactive web-based system with permuted-block randomisation with block size of four. Randomisation was stratified by cT stage, baseline Ki67 score, and progesterone receptor status. A 16-week neoadjuvant phase comprised the same regimen plus palbociclib 125 mg oral daily on days 1-21 of a 28-day cycle, for four cycles. The primary endpoint was geometric mean relative Ki67 score change from baseline to week 2 in patients with complete central Ki67 scores at baseline and week 2 (window-of-opportunity phase). Safety was assessed in all patients who received at least one dose of study drug. The study is registered with ClinicalTrials.gov (NCT04436744) and is complete.
FINDINGS
Between Sept 4, 2020, and June 22, 2021, 221 patients were enrolled and randomly assigned to the giredestrant plus palbociclib group (n=112; median age 62·0 years [IQR 57·0-68·5]) or anastrozole plus palbociclib group (n=109; median age 62·0 [57·0-67·0] years). 15 (7%) of 221 patients were Asian, three (1%) were Black or African American, 194 (88%) were White, and nine (4%) were unknown races. At data cutoff for the primary analysis (July 19, 2021), the geometric mean relative reduction of Ki67 from baseline to week 2 was -75% (95% CI -80 to -70) with giredestrant and -67% (-73 to -59) with anastrozole (p=0·043), meeting the primary endpoint. At the final analysis (data cutoff Nov 24, 2021), the most common grade 3-4 adverse events were neutropenia (29 [26%] of 112 in the giredestrant plus palbociclib group vs 29 [27%] of 109 in the anastrozole plus palbociclib group) and decreased neutrophil count (17 [15%] vs 16 [15%]). Serious adverse events occurred in five (4%) patients in the giredestrant plus palbociclib group and in two (2%) patients in the anastrozole plus palbociclib group. There were no treatment-related deaths. One patient died due to an adverse event in the giredestrant plus palbociclib group (myocardial infarction).
INTERPRETATION
Giredestrant offers encouraging anti-proliferative and anti-tumour activity and was well tolerated, both as a single agent and in combination with palbociclib. Results justify further investigation in ongoing trials.
FUNDING
F Hoffmann-La Roche.
Topics: Humans; Female; Middle Aged; Anastrozole; Breast Neoplasms; Receptors, Estrogen; Neoadjuvant Therapy; Ki-67 Antigen
PubMed: 37657462
DOI: 10.1016/S1470-2045(23)00268-1 -
Clinical Cancer Research : An Official... Aug 2017Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor-positive (ER) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna)...
Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor-positive (ER) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Eligible patients with clinical stage II/III ER/HER2 breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1-21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect. .
Topics: Adult; Aged; Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Proliferation; Class I Phosphatidylinositol 3-Kinases; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase 6; Disease-Free Survival; Estrogen Receptor alpha; Female; Gene Expression Regulation, Neoplastic; Humans; Middle Aged; Mutation; Neoadjuvant Therapy; Neoplasm Staging; Nitriles; Piperazines; Pyridines; Receptor, ErbB-2; Triazoles
PubMed: 28270497
DOI: 10.1158/1078-0432.CCR-16-3206 -
JAMA Oncology Jul 2022Endometrial cancer is often hormone-dependent and treated with aromatase inhibitors. The PI3K-AKT-mTOR pathway deregulation observed in endometrial cancer drives... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety and Efficacy of the mTOR Inhibitor, Vistusertib, Combined With Anastrozole in Patients With Hormone Receptor-Positive Recurrent or Metastatic Endometrial Cancer: The VICTORIA Multicenter, Open-label, Phase 1/2 Randomized Clinical Trial.
IMPORTANCE
Endometrial cancer is often hormone-dependent and treated with aromatase inhibitors. The PI3K-AKT-mTOR pathway deregulation observed in endometrial cancer drives hormonal resistance, thus supporting the rationale of combining mTOR inhibitor with endocrine therapy.
OBJECTIVE
To evaluate the safety and efficacy of vistusertib in combination with anastrozole in the treatment of women with hormone receptor-positive recurrent or metastatic endometrial cancer.
DESIGN, SETTINGS, AND PARTICIPANTS
The VICTORIA study was a multicenter, open-label, randomized clinical trial that accrued 75 patients with hormone receptor-positive recurrent or metastatic endometrial cancer from 12 cancer centers in France in April 2016 to October 2019. After a safety run-in period, a Simon 2-stage design was used. Data analyses were performed from December 11, 2020, to March 11, 2021.
INTERVENTIONS
Patients were randomized in a 2:1 ratio to oral vistusertib (125 mg twice daily 2 days per week) and oral anastrozole (1 mg daily) in the combination vistusertib with anastrozole arm (V+A arm) or oral anastrozole alone (A arm).
MAIN OUTCOMES AND MEASURES
The primary end point was serious adverse events for the safety run-in period and progression-free rate at 8 weeks (8wk-PFR)-assessed with a blinded independent central review in phase 2. The secondary end points were objective response rate, duration of response, progression-free survival (PFS), overall survival, and incidence of adverse events.
RESULTS
Of the 75 patients who were randomized, 73 (median [range] age, 69.5 [37-88] y; all female) were treated: V+A arm, 49 patients; A arm, 24 patients. In the V+A arm, the 8wk-PFR was 67.3% (unilateral 95% CI, 54.7%) and in the A arm, 39.1% (unilateral 95% CI, 22.2%). No significant serious adverse events were reported during the safety run-in period (n = 6 in V+A arm). The overall response rate was 24.5% (95% CI, 13.3%-38.9%) in the V+A arm vs 17.4% (95% CI, 5.0%-38.8%) in the A arm. With a median follow-up of 27.7 months, median PFS was 5.2 (95% CI, 3.4-8.9) in the V+A arm and 1.9 (95% CI, 1.6-8.9) months in the A arm. Fatigue, lymphopenia, hyperglycemia, and diarrhea were the most common (grade ≥2) adverse events associated with vistusertib.
CONCLUSIONS AND RELEVANCE
This multicenter, open-label, phase 1/2 randomized clinical trial demonstrated that adding vistusertib to anastrozole improved 8wk-PFR, overall response rate, and PFS for patients with endometrial cancer and had manageable adverse events. Identification of molecular subgroups would allow for more precise selection of patients who may be most likely to experience favorable outcomes.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02730923.
Topics: Aged; Anastrozole; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Breast Neoplasms; Endometrial Neoplasms; Female; Humans; MTOR Inhibitors; Morpholines; Phosphatidylinositol 3-Kinases; Pyrimidines; TOR Serine-Threonine Kinases
PubMed: 35551299
DOI: 10.1001/jamaoncol.2022.1047