Cynthia Huang Bartlett

AstraZeneca (United States)

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Nicholas C. Turner

Royal Marsden NHS Foundation Trust

María Koehler

Telesta Therapeutics (Canada)

Massimo Cristofanilli

Weill Cornell Medicine

Sherene Loi

Peter MacCallum Cancer Centre

Matthew P. Goetz

Mayo Clinic in Arizona

Sibylle Loibl

German Breast group

Rebecca Aft

Barnes-Jewish Hospital

Helen Krontiras

University of Alabama at Birmingham

Timothy J. Moynihan

Mayo Clinic in Arizona

Hussam Al‐Kateb

Mayo Clinic in Arizona

Cooperative Institutions

Pfizer (United States)

Institute of Cancer Research

Dana-Farber Cancer Institute

GEICAM – Spanish Breast Cancer Group

Royal Marsden Hospital

Washington University in St. Louis

Harvard University

Memorial Sloan Kettering Cancer Center

Royal Marsden NHS Foundation Trust

Breast Cancer Now

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Efficacy and safety of palbociclib in combination with letrozole as first-line treatment of ER-positive, HER2-negative, advanced breast cancer: expanded analyses of subgroups from the randomized pivotal trial PALOMA-1/TRIO-18

Breast Cancer Research (2016)

Richard S. Finn John Crown Johannes Ettl Marcus Schmidt Igor Bondarenko

Palbociclib is an oral small-molecule inhibitor of cyclin-dependent kinases 4 and 6. In the randomized, open-label, phase II PALOMA-1/TRIO-18 trial, palbociclib in combination with letrozole improved progression-free survival (PFS) compared with letrozole alone as first-line treatment of estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative, advanced breast cancer (20.2 months versus 10.2 months; hazard ratio (HR) = 0.488, 95 % confidence interval (CI) 0.319–0.748; one-sided p = 0.0004). Grade 3–4 neutropenia was the most common adverse event (AE) in the palbociclib + letrozole arm. We now present efficacy and safety analyses based on several specific patient and tumor characteristics, and present in detail the clinical patterns of neutropenia observed in the palbociclib + letrozole arm of the overall safety population. Postmenopausal women (n = 165) with ER+, HER2-negative, advanced breast cancer who had not received any systemic treatment for their advanced disease were randomized 1:1 to receive either palbociclib in combination with letrozole or letrozole alone. Treatment continued until disease progression, unacceptable toxicity, consent withdrawal, or death. The primary endpoint was PFS. We now analyze the difference in PFS for the treatment populations by subgroups, including age, histological type, history of prior neoadjuvant/adjuvant systemic treatment, and sites of distant metastasis, using the Kaplan-Meier method. HR and 95 % CI are derived from a Cox proportional hazards regression model. A clinically meaningful improvement in median PFS and clinical benefit response (CBR) rate was seen with palbociclib + letrozole in every subgroup evaluated. Grade 3–4 neutropenia was the most common AE with palbociclib + letrozole in all subgroups. Analysis of the frequency of neutropenia by grade during the first six cycles of treatment showed that there was a downward trend in Grade 3–4 neutropenia over time. Among those who experienced Grade 3–4 neutropenia, 71.7 % had no overlapping infections of any grade and none had overlapping Grade 3–4 infections. The magnitude of clinical benefit seen with the addition of palbociclib to letrozole in improving both median PFS and CBR rate is consistent in nearly all subgroups analyzed, and consistent with that seen in the overall study population. The safety profile of the combination treatment in all subgroups was also comparable to that in the overall safety population of the study.

Palbociclib

Letrozole

Clinical endpoint

Progression-free survival

10.1186/s13058-016-0721-5

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Citations (164)

Data from Biomarker Analyses of Response to Cyclin-Dependent Kinase 4/6 Inhibition and Endocrine Therapy in Women with Treatment-Naïve Metastatic Breast Cancer

Richard S. Finn Yuan Liu Zhou Zhu Miguel Martín Hope S. Rugo

<div>AbstractPurpose:Preclinical data identified the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib as synergistic with antiestrogens in inhibiting growth of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) human breast cancer models. This observation was validated clinically in the randomized, placebo-controlled, phase III PALOMA-2 study.Experimental Design:To determine markers of sensitivity and resistance to palbociclib plus letrozole, we performed comprehensive biomarker analyses, investigating the correlation with progression-free survival (PFS), on baseline tumor tissues from PALOMA-2.Results:Despite a broad biomarker search, palbociclib plus letrozole demonstrated consistent PFS gains versus placebo plus letrozole, with no single biomarker or cassette of markers associated with lack of benefit from combination treatment. Palbociclib plus letrozole confers efficacy on both luminal A and B patients. Higher CDK4 levels were associated with endocrine resistance which was mitigated by the addition of palbociclib, whereas lower PD-1 levels were associated with greater palbociclib plus letrozole benefit. Tumors with more active growth factor signaling, as exemplified by increased expression of FGFR2 and ERBB3 mRNA, appeared to be associated with greater PFS gain from the addition of palbociclib.Conclusions:These data underscore the importance of CDK4/6 signaling in HR+/HER2− breast cancer and suggest that the interplay between steroid hormone and peptide growth factor signaling could drive dependence on CDK4/6 signaling.See related commentary by Anurag et al., p. 3</div>

Palbociclib

Letrozole

Cyclin-dependent kinase 4

10.1158/1078-0432.c.6528555.v1

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Biomarker Analyses of Response to Cyclin-Dependent Kinase 4/6 Inhibition and Endocrine Therapy in Women with Treatment-Naïve Metastatic Breast Cancer

Clinical Cancer Research (2019)

Richard S. Finn Yuan Liu Zhou Zhu Miguel Martín Hope S. Rugo

Abstract Purpose: Preclinical data identified the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib as synergistic with antiestrogens in inhibiting growth of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) human breast cancer models. This observation was validated clinically in the randomized, placebo-controlled, phase III PALOMA-2 study. Experimental Design: To determine markers of sensitivity and resistance to palbociclib plus letrozole, we performed comprehensive biomarker analyses, investigating the correlation with progression-free survival (PFS), on baseline tumor tissues from PALOMA-2. Results: Despite a broad biomarker search, palbociclib plus letrozole demonstrated consistent PFS gains versus placebo plus letrozole, with no single biomarker or cassette of markers associated with lack of benefit from combination treatment. Palbociclib plus letrozole confers efficacy on both luminal A and B patients. Higher CDK4 levels were associated with endocrine resistance which was mitigated by the addition of palbociclib, whereas lower PD-1 levels were associated with greater palbociclib plus letrozole benefit. Tumors with more active growth factor signaling, as exemplified by increased expression of FGFR2 and ERBB3 mRNA, appeared to be associated with greater PFS gain from the addition of palbociclib. Conclusions: These data underscore the importance of CDK4/6 signaling in HR+/HER2− breast cancer and suggest that the interplay between steroid hormone and peptide growth factor signaling could drive dependence on CDK4/6 signaling. See related commentary by Anurag et al., p. 3

Palbociclib

Letrozole

Cyclin-dependent kinase 4

Fulvestrant

10.1158/1078-0432.ccr-19-0751

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Citations (155)

Experience of implementing a novel random sampling BICR audit for investigator (INV)-assessed progression-free survival (PFS) in the PALOMA-3 trial.

Journal of Clinical Oncology (2017)

Xin Huang Ke Zhang Nicholas C. Turner Cynthia Huang Bartlett C. Giorgetti

1058 Background: PFS has frequently been used as a primary endpoint for evaluating efficacy of anticancer therapies in randomized clinical trials. Given high correlation between INV and independent (BICR) assessments with respect to the relative treatment effect, a pre-planned BICR audit of INV progression assessment in a random subgroup of patients (pts) instead of a BICR review of all progression assessments can be an acceptable approach to verify the INV assessments and to evaluate the potential bias in INV PFS results. Methods: PALOMA-3 was a randomized, double blind, placebo (PCB) controlled, Ph 3 study with the primary objective of demonstrating the superiority of palbociclib (PAL) + fulvestrant (F) over PCB + F in women with HR+, HER2- metastatic breast cancer (MBC). The primary endpoint was INV assessed PFS. BICR assessment of PFS was performed with the use of a novel audit approach involving a random sample–based BICR to verify if the INV assessed PFS was accurate. A third-party core imaging laboratory performed the blinded review for a randomly selected subgroup of pts (~40%). NIH and PhRMA methods were used to evaluate the potential for bias in the INV PFS results. Results: PAL + F improved PFS in patients with HR+, HER2- MBC. The observed INV HR was 0.46 (95% CI: 0.36, 0.59; stratified 1-sided p < 0.0001) in favor of PAL + F. The median PFS was 9.5 mo (95% CI: 9.2, 11.0) in the PAL + F arm and 4.6 mo (95% CI: 3.5, 5.6) in the PCB + F arm (Lancet Oncol. 2016; 17: 425–39). The estimated HR of the complete BICR data incorporating the information from the complete INV assessed PFS and the random sample audited BICR subgroup was 0.33 with the upper bound of the 1-sided 95% CI of 0.47. The results confirmed the INV assessed treatment effect and detected no INV bias in favor of PAL + F. Conclusions: PALOMA-3 is the first registrational trial to use a BICR audit and has received positive reviews from regulatory agencies. The experience of implementing the random sampling BICR audit in PALOMA-3 demonstrates that this approach can be used for randomized, double blind oncology trials with solid tumors where INV assessed PFS is the primary endpoint and a large treatment effect is targeted. Sponsor: Pfizer. Clinical trial information: NCT01942135.

Fulvestrant

Clinical endpoint

Palbociclib

Progression-free survival

10.1200/jco.2017.35.15_suppl.1058

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Data from The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial

Ben O’Leary Rosalind J. Cutts Yuan Liu Sarah Hrebien Xin Huang

<div>AbstractCDK4/6 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. RB1 mutations emerged only in the palbociclib plus fulvestrant arm and in a minority of patients (6/127, 4.7%, P = 0.041). New driver mutations emerged in PIK3CA (P = 0.00069) and ESR1 after treatment in both arms, in particular ESR1 Y537S (P = 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.Significance: Acquired mutations from fulvestrant are a major driver of resistance to fulvestrant and palbociclib combination therapy. ESR1 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. Cancer Discov; 8(11); 1390–403. ©2018 AACR.See related commentary by Schiff and Jeselsohn, p. 1352.This article is highlighted in the In This Issue feature, p. 1333</div>

Palbociclib

Fulvestrant

10.1158/2159-8290.c.6546599.v1

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Real‐World Data of Palbociclib in Combination With Endocrine Therapy for the Treatment of Metastatic Breast Cancer in Men

Clinical Pharmacology & Therapeutics (2021)

Albert L. Kraus Michelle Yu‐Kite Jack Mardekian Matthew J. Cotter Sindy Kim

This report examined the benefits and risks of palbociclib plus endocrine therapy (ET) in men with hormone receptor‒positive (HR+)/human epidermal growth factor receptor 2−negative (HER2−) metastatic breast cancer (MBC). Palbociclib was evaluated using three independent data sources: real‐world data from pharmacy and medical claims, a de‐identified real‐world data source derived from electronic health records (EHRs), and a global safety database. From medical and pharmacy records, 1,139 men with MBC were identified; in the first‐line setting, median duration of treatment was longer with palbociclib plus ET ( n = 37, 8.5 months, 95% confidence interval (CI), 4.4‒13.0) than ET alone ( n = 214, 4.3 months, 95% CI, 3.0‒5.7) and specifically, was longer with palbociclib plus letrozole ( n = 26, 9.4 months, 95% CI, 4.4‒14.0) than letrozole alone ( n = 63, 3.0 months, 95% CI, 1.8‒4.8). In the EHR‐derived database, 59 men received treatment for MBC; real‐world response across all lines of therapy in the metastatic setting was reported in 4 of 12 patients (33.3%) in the palbociclib plus ET group vs. 1 of 8 (12.5%) patients in the ET group. Review of the global safety database did not identify any new safety signals in palbociclib‐treated men. Real‐world data indicated that men with MBC benefit from palbociclib plus ET, with a safety profile consistent with previous observations in women with MBC. Collective data on palbociclib in women and men in this report, including clinical trial data, real‐world data, and a well‐established risk/benefit profile, led to US approval of an expansion of the palbociclib indication to include men with MBC.

Palbociclib

Letrozole

10.1002/cpt.2454

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Citations (32)

A Large Retrospective Analysis of Pemetrexed (PEM) Activity in Patients (PTS) with Alk-Positive (Alk+) Non-Small Cell Lung Cancer (NSCLC) Prior to Crizotinib (CRIZ) Treatment

Annals of Oncology (2012)

Giorgio V. Scagliotti D.W. Kim Alice T. Shaw S-H.I. Ou Gregory J. Riely

Pemetrexed

ALK inhibitor

10.1016/s0923-7534(20)33862-x

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Citations (1)

Comparison of BEAMing and Droplet Digital PCR for Circulating Tumor DNA Analysis

Clinical Chemistry (2019)

Ben O’Leary Sarah Hrebien Matthew Beaney Charlotte Fribbens Isaac García-Murillas

Circulating tumor DNA (ctDNA) assays are increasingly used for clinical decision-making, but it is unknown how well different assays agree. We aimed to assess the agreement in ctDNA mutation calling between BEAMing (beads, emulsion, amplification, and magnetics) and droplet digital PCR (ddPCR), 2 of the most commonly used digital PCR techniques for detecting mutations in ctDNA.Baseline plasma samples from patients with advanced breast cancer enrolled in the phase 3 PALOMA-3 trial were assessed for ESR1 and PIK3CA mutations in ctDNA with both BEAMing and ddPCR. Concordance between the 2 approaches was assessed, with exploratory analyses to estimate the importance of sampling effects.Of the 521 patients enrolled, 363 had paired baseline ctDNA analysis. ESR1 mutation detection was 24.2% (88/363) for BEAMing and 25.3% (92/363) for ddPCR, with good agreement between the 2 techniques (κ = 0.9l; 95% CI, 0.85-0.95). PIK3CA mutation detection rates were 26.2% (95/363) for BEAMing and 22.9% (83/363) for ddPCR, with good agreement (κ = 0.87; 95% CI, 0.81-0.93). Discordancy was observed for 3.9% patients with ESR1 mutations and 5.0% with PIK3CA mutations. Assessment of individual mutations suggested higher rates of discordancy for less common mutations (P = 0.019). The majority of discordant calls occurred at allele frequency <1%, predominantly resulting from stochastic sampling effects.This large, clinically relevant comparison showed good agreement between BEAMing and ddPCR, suggesting sufficient reproducibility for clinical use. Much of the observed discordancy may be related to sampling effects, potentially explaining many of the differences in the currently available ctDNA literature.

Concordance

10.1373/clinchem.2019.305805

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Citations (76)

Data from The Genetic Landscape and Clonal Evolution of Breast Cancer Resistance to Palbociclib plus Fulvestrant in the PALOMA-3 Trial

Ben O’Leary Rosalind J. Cutts Yuan Liu Sarah Hrebien Xin Huang

Palbociclib

Fulvestrant

10.1158/2159-8290.c.6546599

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Citations (0)

Supplementary Tables S1 and S2 from NeoPalAna: Neoadjuvant Palbociclib, a Cyclin-Dependent Kinase 4/6 Inhibitor, and Anastrozole for Clinical Stage 2 or 3 Estrogen Receptor–Positive Breast Cancer