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The Lancet. Oncology Jul 2022Capivasertib, an AKT inhibitor, added to fulvestrant, was previously reported to improve progression-free survival in women with aromatase inhibitor-resistant oestrogen... (Randomized Controlled Trial)
Randomized Controlled Trial
Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2...
BACKGROUND
Capivasertib, an AKT inhibitor, added to fulvestrant, was previously reported to improve progression-free survival in women with aromatase inhibitor-resistant oestrogen receptor (ER)-positive, HER2-negative advanced breast cancer. The benefit appeared to be independent of the phosphoinositide 3-kinase (PI3K)/AKT/phosphatase and tensin homologue (PTEN) pathway alteration status of tumours, as ascertained using assays available at the time. Here, we report updated progression-free survival and overall survival results, and a prespecified examination of the effect of PI3K/AKT/PTEN pathway alterations identified by an expanded genetic testing panel on treatment outcomes.
METHODS
This randomised, multicentre, double-blind, placebo-controlled, phase 2 trial recruited postmenopausal adult women aged at least 18 years with ER-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2, who had relapsed or progressed on an aromatase inhibitor, from across 19 hospitals in the UK. Participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a 500 mg loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off, starting on cycle 1 day 15. Treatment continued until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment was allocated by an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival in the intention-to-treat population. Secondary endpoints shown in this Article were overall survival and safety in the intention-to-treat population, and the effect of tumour PI3K/AKT/PTEN pathway status identified by an expanded testing panel that included next-generation sequencing assays. Recruitment is complete. The trial is registered with ClinicalTrials.gov, number NCT01992952.
FINDINGS
Between March 16, 2015, and March 6, 2018, 183 participants were screened for eligibility and 140 (77%) were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up at the data cut-off of Nov 25, 2021, was 58·5 months (IQR 45·9-64·1) for participants treated with fulvestrant plus capivasertib and 62·3 months (IQR 62·1-70·3) for fulvestrant plus placebo. Updated median progression-free survival was 10·3 months (95% CI 5·0-13·4) in the group receiving fulvestrant plus capivasertib compared with 4·8 months (3·1-7·9) for fulvestrant plus placebo (adjusted hazard ratio [HR] 0·56 [95% CI 0·38-0·81]; two-sided p=0·0023). Median overall survival in the capivasertib versus placebo groups was 29·3 months (95% CI 23·7-39·0) versus 23·4 months (18·7-32·7; adjusted HR 0·66 [95% CI 0·45-0·97]; two-sided p=0·035). The expanded biomarker panel identified an expanded pathway-altered subgroup that contained 76 participants (54% of the intention-to-treat population). Median progression-free survival in the expanded pathway-altered subgroup for participants receiving capivasertib (n=39) was 12·8 months (95% CI 6·6-18·8) compared with 4·6 months (2·8-7·9) in the placebo group (n=37; adjusted HR 0·44 [95% CI 0·26-0·72]; two-sided p=0·0014). Median overall survival for the expanded pathway-altered subgroup receiving capivasertib was 38·9 months (95% CI 23·3-50·7) compared with 20·0 months (14·8-31·4) for those receiving placebo (adjusted HR 0·46 [95% CI 0·27-0·79]; two-sided p=0·0047). By contrast, there were no statistically significant differences in progression-free or overall survival in the expanded pathway non-altered subgroup treated with capivasertib (n=30) versus placebo (n=34). One additional serious adverse event (pneumonia) in the capivasertib group had occurred subsequent to the primary analysis. One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment.
INTERPRETATION
Updated FAKTION data showed that capivasertib addition to fulvestrant extends the survival of participants with aromatase inhibitor-resistant ER-positive, HER2-negative advanced breast cancer. The expanded biomarker testing suggested that capivasertib predominantly benefits patients with PI3K/AKT/PTEN pathway-altered tumours. Phase 3 data are needed to substantiate the results, including in patients with previous CDK4/6 inhibitor exposure who were not included in the FAKTION trial.
FUNDING
AstraZeneca and Cancer Research UK.
Topics: Adolescent; Adult; Antineoplastic Combined Chemotherapy Protocols; Aromatase Inhibitors; Breast Neoplasms; Double-Blind Method; Female; Fulvestrant; Humans; Neoplasm Recurrence, Local; Phosphatidylinositol 3-Kinases; Progression-Free Survival; Proto-Oncogene Proteins c-akt; Pyrimidines; Pyrroles; Receptor, ErbB-2; Receptors, Estrogen
PubMed: 35671774
DOI: 10.1016/S1470-2045(22)00284-4 -
Chirurgia (Bucharest, Romania : 1990) 2017Hormonal therapy is mandatory for all patients with hormonereceptor- positive breast neoplasms. It is active both in adjuvant and metastatic disease. The only active... (Review)
Review
Hormonal therapy is mandatory for all patients with hormonereceptor- positive breast neoplasms. It is active both in adjuvant and metastatic disease. The only active adjuvant hormonal therapy in pre- and postmenopause is Tamoxifen. The adjuvant treatment duration influences disease-free survival, the risk of a contralateral breast cancer apparition and overall survival. The aromatase inhibitors: Anastrozol, Letrozol, Exemestan are only used in postmenopause. Fulvestrant is used in recurrent disease after or during treatment with Tamoxifen. LHRH analogues are used in premenopausal patients in adjuvantcy and sometimes in case of recurrences. Around 50% of hormonereceptor- positive breast neoplasms are or become resistant to hormone therapy. Some molecules involved in some tumour cellular growth pathways reverse the resistance to hormone therapy (Palbociclib, Everolimus).
Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Chemotherapy, Adjuvant; Disease-Free Survival; Estradiol; Female; Fulvestrant; Gonadotropin-Releasing Hormone; Humans; Postmenopause; Premenopause; Quality of Life; Tamoxifen; Treatment Outcome
PubMed: 28862117
DOI: 10.21614/chirurgia.112.4.413 -
Annals of Oncology : Official Journal... Feb 2021Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor... (Randomized Controlled Trial)
Randomized Controlled Trial
Alpelisib plus fulvestrant for PIK3CA-mutated, hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced breast cancer: final overall survival results from SOLAR-1.
BACKGROUND
Activation of the phosphatidylinositol-3-kinase (PI3K) pathway via PIK3CA mutations occurs in 28%-46% of hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancers (ABCs) and is associated with poor prognosis. The SOLAR-1 trial showed that the addition of alpelisib to fulvestrant treatment provided statistically significant and clinically meaningful progression-free survival (PFS) benefit in PIK3CA-mutated, HR+, HER2- ABC.
PATIENTS AND METHODS
Men and postmenopausal women with HR+, HER2- ABC whose disease progressed on or after aromatase inhibitor (AI) were randomized 1 : 1 to receive alpelisib (300 mg/day) plus fulvestrant (500 mg every 28 days and once on day 15) or placebo plus fulvestrant. Overall survival (OS) in the PIK3CA-mutant cohort was evaluated by Kaplan-Meier methodology and a one-sided stratified log-rank test was carried out with an O'Brien-Fleming efficacy boundary of P ≤ 0.0161.
RESULTS
In the PIK3CA-mutated cohort (n = 341), median OS [95% confidence interval (CI)] was 39.3 months (34.1-44.9) for alpelisib-fulvestrant and 31.4 months (26.8-41.3) for placebo-fulvestrant [hazard ratio (HR) = 0.86 (95% CI, 0.64-1.15; P = 0.15)]. OS results did not cross the prespecified efficacy boundary. Median OS (95% CI) in patients with lung and/or liver metastases was 37.2 months (28.7-43.6) and 22.8 months (19.0-26.8) in the alpelisib-fulvestrant and placebo-fulvestrant arms, respectively [HR = 0.68 (0.46-1.00)]. Median times to chemotherapy (95% CI) for the alpelisib-fulvestrant and placebo-fulvestrant arms were 23.3 months (15.2-28.4) and 14.8 months (10.5-22.6), respectively [HR = 0.72 (0.54-0.95)]. No new safety signals were observed with longer follow-up.
CONCLUSIONS
Although the analysis did not cross the prespecified boundary for statistical significance, there was a 7.9-month numeric improvement in median OS when alpelisib was added to fulvestrant treatment of patients with PIK3CA-mutated, HR+, HER2- ABC. Overall, these results further support the statistically significant prolongation of PFS observed with alpelisib plus fulvestrant in this population, which has a poor prognosis due to a PIK3CA mutation. CLINICALTRIALS.
GOV ID
NCT02437318.
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Class I Phosphatidylinositol 3-Kinases; Female; Fulvestrant; Humans; Male; Receptor, ErbB-2; Receptors, Estrogen; Thiazoles
PubMed: 33246021
DOI: 10.1016/j.annonc.2020.11.011 -
Nature Jul 2020Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive...
Approximately 75% of all breast cancers express the oestrogen and/or progesterone receptors. Endocrine therapy is usually effective in these hormone-receptor-positive tumours, but primary and acquired resistance limits its long-term benefit. Here we show that in mouse models of hormone-receptor-positive breast cancer, periodic fasting or a fasting-mimicking diet enhances the activity of the endocrine therapeutics tamoxifen and fulvestrant by lowering circulating IGF1, insulin and leptin and by inhibiting AKT-mTOR signalling via upregulation of EGR1 and PTEN. When fulvestrant is combined with palbociclib (a cyclin-dependent kinase 4/6 inhibitor), adding periodic cycles of a fasting-mimicking diet promotes long-lasting tumour regression and reverts acquired resistance to drug treatment. Moreover, both fasting and a fasting-mimicking diet prevent tamoxifen-induced endometrial hyperplasia. In patients with hormone-receptor-positive breast cancer receiving oestrogen therapy, cycles of a fasting-mimicking diet cause metabolic changes analogous to those observed in mice, including reduced levels of insulin, leptin and IGF1, with the last two remaining low for extended periods. In mice, these long-lasting effects are associated with long-term anti-cancer activity. These results support further clinical studies of a fasting-mimicking diet as an adjuvant to oestrogen therapy in hormone-receptor-positive breast cancer.
Topics: Animals; Biological Factors; Breast Neoplasms; Diet Therapy; Diet, Healthy; Disease Models, Animal; Disease Progression; Drug Resistance, Neoplasm; Early Growth Response Protein 1; Fasting; Female; Fulvestrant; Humans; Insulin; Insulin-Like Growth Factor I; Leptin; MCF-7 Cells; Mice, Inbred NOD; Mice, SCID; PTEN Phosphohydrolase; Piperazines; Pyridines; Receptors, Estrogen; Receptors, Progesterone; Tamoxifen; Xenograft Model Antitumor Assays
PubMed: 32669709
DOI: 10.1038/s41586-020-2502-7 -
Clinical Cancer Research : An Official... Aug 2022To conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
To conduct an updated exploratory analysis of overall survival (OS) with a longer median follow-up of 73.3 months and evaluate the prognostic value of molecular analysis by circulating tumor DNA (ctDNA).
PATIENTS AND METHODS
Patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC) were randomized 2:1 to receive palbociclib (125 mg orally/day; 3/1 week schedule) and fulvestrant (500 mg intramuscularly) or placebo and fulvestrant. This OS analysis was performed when 75% of enrolled patients died (393 events in 521 randomized patients). ctDNA analysis was performed among patients who provided consent.
RESULTS
At the data cutoff (August 17, 2020), 258 and 135 deaths occurred in the palbociclib and placebo groups, respectively. The median OS [95% confidence interval (CI)] was 34.8 months (28.8-39.9) in the palbociclib group and 28.0 months (23.5-33.8) in the placebo group (stratified hazard ratio, 0.81; 95% CI, 0.65-0.99). The 6-year OS rate (95% CI) was 19.1% (14.9-23.7) and 12.9% (8.0-19.1) in the palbociclib and placebo groups, respectively. Favorable OS with palbociclib plus fulvestrant compared with placebo plus fulvestrant was observed in most subgroups, particularly in patients with endocrine-sensitive disease, no prior chemotherapy for ABC and low circulating tumor fraction and regardless of ESR1, PIK3CA, or TP53 mutation status. No new safety signals were identified.
CONCLUSIONS
The clinically meaningful improvement in OS associated with palbociclib plus fulvestrant was maintained with >6 years of follow-up in patients with HR+/HER2- ABC, supporting palbociclib plus fulvestrant as a standard of care in these patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Double-Blind Method; Female; Fulvestrant; Humans; Piperazines; Pyridines; Receptor, ErbB-2
PubMed: 35552673
DOI: 10.1158/1078-0432.CCR-22-0305 -
Cancer Nov 2019The acquisition of ligand-independent ESR1 mutations during aromatase inhibitor therapy in metastatic estrogen receptor (ER)-positive breast cancer is a common mechanism... (Review)
Review
The acquisition of ligand-independent ESR1 mutations during aromatase inhibitor therapy in metastatic estrogen receptor (ER)-positive breast cancer is a common mechanism of hormonal therapy resistance. Preclinical and clinical studies have demonstrated that ESR1 mutations can preexist in primary tumors and can be enriched during metastasis. Furthermore, ESR1 mutations express a unique transcriptional profile that favors tumor progression, suggesting that selected ESR1 mutations may influence metastasis. Several groups have used sensitive detection methods using patient liquid biopsies to track ESR1 or truncal somatic mutations to predict treatment outcome and tumor progression, and some of these techniques may eventually be used to guide sequential treatment options in patients. Further development and standardization of mutation tracking in circulating tumor DNA is ongoing. Clinically, patients with ESR1 mutations derive clinical benefit when treated with fulvestrant and CDK4/6-targeted therapies, but the development of more potent selective ER degraders and/or new targeted biotherapies are needed to overcome the endocrine-resistant phenotype of ESR1 mutant-bearing tumors. In this review, we discuss the mechanisms of resistance and dissemination of ESR1 mutations as well as the detection methods for ESR1 mutation tracking, newly discovered potential therapeutic targets, and the clinical implications and treatment options for treating patients with ESR1 mutant-bearing tumors.
Topics: Antineoplastic Agents, Hormonal; Breast Neoplasms; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Female; Fulvestrant; Gene Expression Profiling; Humans; Liquid Biopsy; Mutation; Protein Kinase Inhibitors
PubMed: 31318440
DOI: 10.1002/cncr.32345 -
Annals of Oncology : Official Journal... Aug 2021Ribociclib plus fulvestrant demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits in patients with hormone receptor-positive, human... (Randomized Controlled Trial)
Randomized Controlled Trial
Ribociclib plus fulvestrant for postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer in the phase III randomized MONALEESA-3 trial: updated overall survival.
BACKGROUND
Ribociclib plus fulvestrant demonstrated significant progression-free survival (PFS) and overall survival (OS) benefits in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). Here we present a new landmark in survival follow-up for a phase III cyclin-dependent kinases 4 and 6 inhibitor clinical trial in patients with ABC (median, 56.3 months).
PATIENTS AND METHODS
This phase III, randomized, double-blind, placebo-controlled trial was conducted at 174 sites (30 countries). Patients were men and postmenopausal women (age ≥18 years) with histologically/cytologically confirmed HR+/HER2- ABC. Patients could have received ≤1 line of endocrine therapy (ET) but no chemotherapy for ABC. Patients, assigned 2:1, were stratified by the presence/absence of liver/lung metastases and previous ET. Patients received intramuscular fulvestrant (500 mg, day 1 of each 28-day cycle plus day 15 of cycle 1) with oral ribociclib (600 mg/day, 3 weeks on, 1 week off) or placebo. Efficacy analyses were by intention to treat. Safety was assessed in patients receiving ≥1 dose study treatment. OS was a secondary endpoint. MONALEESA-3 is registered with ClinicalTrials.gov (NCT02422615; no longer enrolling).
RESULTS
Between 18 June 2015 and 10 June 2016, 726 patients were randomly assigned (484, ribociclib; 242, placebo). At data cut-off (30 October 2020), median OS (mOS) was 53.7 months (ribociclib) versus 41.5 months (placebo) [hazard ratio (HR), 0.73; 95% confidence interval (CI) 0.59-0.90]. Subgroup analyses were consistent with overall population. In the first-line setting, most patients in the ribociclib arm (∼60%) lived longer than median follow-up; mOS was 51.8 months in the placebo arm (HR, 0.64; 95% CI 0.46-0.88). In the second-line setting, mOS was 39.7 months (ribociclib) versus 33.7 months (placebo) (HR, 0.78; 95% CI 0.59-1.04). No apparent drug-drug interaction between ribociclib and fulvestrant or new safety signals were observed.
CONCLUSIONS
This analysis reported extended OS follow-up in MONALEESA-3. mOS was ∼12 months longer in patients with HR+/HER2- ABC treated with ribociclib plus fulvestrant compared with fulvestrant monotherapy.
Topics: Adolescent; Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Double-Blind Method; Female; Fulvestrant; Humans; Postmenopause; Purines; Receptor, ErbB-2; Receptors, Estrogen; Receptors, Progesterone
PubMed: 34102253
DOI: 10.1016/j.annonc.2021.05.353 -
JAMA Oncology Jan 2020Statistically significant overall survival (OS) benefits of CDK4 and CDK6 inhibitors in combination with fulvestrant for hormone receptor (HR)-positive, ERBB2 (formerly... (Randomized Controlled Trial)
Randomized Controlled Trial
The Effect of Abemaciclib Plus Fulvestrant on Overall Survival in Hormone Receptor-Positive, ERBB2-Negative Breast Cancer That Progressed on Endocrine Therapy-MONARCH 2: A Randomized Clinical Trial.
IMPORTANCE
Statistically significant overall survival (OS) benefits of CDK4 and CDK6 inhibitors in combination with fulvestrant for hormone receptor (HR)-positive, ERBB2 (formerly HER2)-negative advanced breast cancer (ABC) in patients regardless of menopausal status after prior endocrine therapy (ET) has not yet been demonstrated.
OBJECTIVE
To compare the effect of abemaciclib plus fulvestrant vs placebo plus fulvestrant on OS at the prespecified interim of MONARCH 2 (338 events) in patients with HR-positive, ERBB2-negative advanced breast cancer that progressed during prior ET.
DESIGN, SETTING, AND PARTICIPANTS
MONARCH 2 was a global, randomized, placebo-controlled, double-blind phase 3 trial of abemaciclib plus fulvestrant vs placebo plus fulvestrant for treatment of premenopausal or perimenopausal women (with ovarian suppression) and postmenopausal women with HR-positive, ERBB2-negative ABC that progressed during ET. Patients were enrolled between August 7, 2014, and December 29, 2015. Analyses for this report were conducted at the time of database lock on June 20, 2019.
INTERVENTIONS
Patients were randomized 2:1 to receive abemaciclib or placebo, 150 mg, every 12 hours on a continuous schedule plus fulvestrant, 500 mg, per label. Randomization was stratified based on site of metastasis (visceral, bone only, or other) and resistance to prior ET (primary vs secondary).
MAIN OUTCOMES AND MEASURES
The primary end point was investigator-assessed progression-free survival. Overall survival was a gated key secondary end point. The boundary P value for the interim analysis was .02.
RESULTS
Of 669 women enrolled, 446 (median [range] age, 59 [32-91] years) were randomized to the abemaciclib plus fulvestrant arm and 223 (median [range] age, 62 [32-87] years) were randomized to the placebo plus fulvestrant arm. At the prespecified interim, 338 deaths (77% of the planned 441 at the final analysis) were observed in the intent-to-treat population, with a median OS of 46.7 months for abemaciclib plus fulvestrant and 37.3 months for placebo plus fulvestrant (hazard ratio [HR], 0.757; 95% CI, 0.606-0.945; P = .01). Improvement in OS was consistent across all stratification factors. Among stratification factors, more pronounced effects were observed in patients with visceral disease (HR, 0.675; 95% CI, 0.511-0.891) and primary resistance to prior ET (HR, 0.686; 95% CI, 0.451-1.043). Time to second disease progression (median, 23.1 months vs 20.6 months), time to chemotherapy (median, 50.2 months vs 22.1 months), and chemotherapy-free survival (median, 25.5 months vs 18.2 months) were also statistically significantly improved in the abemaciclib arm vs placebo arm. No new safety signals were observed for abemaciclib.
CONCLUSIONS AND RELEVANCE
Treatment with abemaciclib plus fulvestrant resulted in a statistically significant and clinically meaningful median OS improvement of 9.4 months for patients with HR-positive, ERBB2-negative ABC who progressed after prior ET regardless of menopausal status. Abemaciclib substantially delayed the receipt of subsequent chemotherapy.
TRIAL REGISTRATION
ClinicalTrials.gov identifier: NCT02107703.
Topics: Aminopyridines; Antineoplastic Combined Chemotherapy Protocols; Benzimidazoles; Breast Neoplasms; Female; Fulvestrant; Humans; Middle Aged; Receptor, ErbB-2; Triple Negative Breast Neoplasms
PubMed: 31563959
DOI: 10.1001/jamaoncol.2019.4782 -
Future Oncology (London, England) Oct 2019Elacestrant is a novel, nonsteroidal, orally bioavailable selective estrogen receptor degrader (SERD) that has demonstrated activity in patients with estrogen receptor...
Elacestrant is a novel, nonsteroidal, orally bioavailable selective estrogen receptor degrader (SERD) that has demonstrated activity in patients with estrogen receptor (ER)-positive/HER2-negative breast cancer previously treated with endocrine therapies including fulvestrant and/or CDK 4/6 inhibitor therapy, and in those with mutations (-mut) known to confer endocrine resistance. Herein, we describe the design and methodology of EMERALD, an international, multicenter, randomized, open-label, active-controlled, Phase III clinical study comparing the efficacy and safety of elacestrant to standard-of-care endocrine monotherapy treatment (fulvestrant or an aromatase inhibitor, per investigator's choice) in patients with ER-positive/HER2-negative advanced breast cancer. Primary end points are progression-free survival in -mut patients and in all patients (NCT03778931; EudraCT 2018-002990-24).
Topics: Female; Humans; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Estrogen Receptor alpha; Follow-Up Studies; Fulvestrant; International Agencies; Prognosis; Prospective Studies; Survival Rate; Tetrahydronaphthalenes; Randomized Controlled Trials as Topic; Multicenter Studies as Topic
PubMed: 31426673
DOI: 10.2217/fon-2019-0370 -
Cancer Discovery Nov 2018CDK4/6 inhibition with endocrine therapy is now a standard of care for advanced estrogen receptor-positive breast cancer. Mechanisms of CDK4/6 inhibitor resistance have... (Randomized Controlled Trial)
Randomized Controlled Trial
CDK4/6 inhibition with endocrine therapy is now a standard of care for advanced estrogen receptor-positive breast cancer. Mechanisms of CDK4/6 inhibitor resistance have been described preclinically, with limited evidence from clinical samples. We conducted paired baseline and end-of-treatment circulating tumor DNA sequencing from 195 patients in the PALOMA-3 randomized phase III trial of palbociclib plus fulvestrant versus placebo plus fulvestrant. We show that clonal evolution occurs frequently during treatment, reflecting substantial subclonal complexity in breast cancer that has progressed after prior endocrine therapy. mutations emerged only in the palbociclib plus fulvestrant arm and in a minority of patients (6/127, 4.7%, = 0.041). New driver mutations emerged in ( = 0.00069) and after treatment in both arms, in particular Y537S ( = 0.0037). Evolution of driver gene mutations was uncommon in patients progressing early on palbociclib plus fulvestrant but common in patients progressing later on treatment. These findings inform future treatment strategies to address resistance to palbociclib plus fulvestrant. Acquired mutations from fulvestrant are a major driver of resistance to fulvestrant and palbociclib combination therapy. Y537S mutation promotes resistance to fulvestrant. Clonal evolution results in frequent acquisition of driver mutations in patients progressing late on therapy, which suggests that early and late progression have distinct mechanisms of resistance. .
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Breast Neoplasms; Clonal Evolution; Double-Blind Method; Drug Resistance, Neoplasm; Estrogen Receptor alpha; Female; Follow-Up Studies; Fulvestrant; Humans; Mutation; Piperazines; Prognosis; Pyridines
PubMed: 30206110
DOI: 10.1158/2159-8290.CD-18-0264