Abstract ctDNA-based DNADX in hormone receptor-positive and HER2-negative (HR+/HER2-) advanced breast cancer following endocrine therapy and CDK4/6 inhibition: a correlative analysis from the randomized phase 2 PARSIFAL trial Background: DNADX, a novel machine learning-based approach, utilizes DNA from tumor tissue or plasma ctDNA to identify clinically relevant phenotypic tumor features and classify breast cancer into 4 subtypes (Nat Comm 2023). Here, we evaluated DNADX's ability to predict prognosis and treatment benefit in HR+/HER2- advanced breast cancer following endocrine therapy and a CDK4/6 inhibitor. Methods: DNADX was evaluated centrally in available baseline plasma ctDNA samples from PARSIFAL trial (NCT02491983) which randomized 486 patients (pts) with HR+/HER2- advanced breast cancer to receive (1:1 ratio) first line palbociclib with either fulvestrant or letrozole. Shallow whole genome sequencing was performed on ctDNA, and the 4 DNA-based subtypes (Clusters-1, -2, -3, and -4) were identified if the ctDNA tumor fraction (TF)≥3%. The main objective was to evaluate the association of DNADX subtypes with progression-free survival (PFS) and overall survival (OS). Secondary objective was to identify the subgroup of pts who benefit more from each endocrine treatment. Uni- and multi-variable Cox regression models were used after adjusting for TF, menopausal status, ECOG status, de novo metastasis (vs. recurrence), visceral disease and number of metastatic sites. Results: DNADX was evaluated in plasma ctDNA samples from 122 pts (25.1%). Clinical variables and median PFS (27.6 months) were similar as the overall PARSIFAL population. DNADX identified 56.6% pts with TF of < 3%, 14.8% with Cluster-1, 19.7% with Cluster-2, 5.7% with Cluster-3 and 3.3% with Cluster-4. In terms of PFS, pts classified with TF< 3% had a lower risk of progression compared to Cluster-1, Cluster-2, Cluster-3, Cluster-4 subtypes (pairwise PFS hazard ratios [HRs] of 1.88, 2.02, 3.15, and 5.62, respectively, with a global log-rank test of p=0.010). Similar results were obtained after adjusting for other clinical-pathologic variables. A numerical benefit of fulvestrant in comparison with letrozole was observed in pts classified in Cluster-1 and Cluster-4 (HR=0.42, 95% CI 0.14-1.24) in contrast to the other groups (HR=1.21, 95% CI 0.68-2.18), and the interaction test was statistically significant after adjusting for clinical-pathologic variables (anova p-value=0.037). In terms of OS, pts classified with TF< 3% had a lower risk of death compared to Cluster-1, Cluster-2, Cluster-3, and Cluster-4 subtypes (pairwise OS HRs of 1.90, 4.23, 11.13, and 6.80, respectively, with a global log-rank test of p=0.003). In the multivariable analysis, results were consistent after adjusting for clinical-pathologic variables and TF. Conclusions: Liquid biopsy-based DNADX subtypes predict outcomes in pts with HR+/HER2- advanced breast cancer on endocrine therapy and CDK4/6 inhibitors, potentially identifying the most optimal endocrine treatment for each pt. Citation Format: Fara Brasó-Maristany, Javier Cortés, José Manuel Pérez-García, Rosario Vega-León, Laia Paré, Guillermo Villacampa, Judit Matito, Francisco Pardo, Marina Gomez-Rey, Mario Mancino, Elena Martínez-García, Carmen Mora Gallardo, Leonardo Mina, Florence Dalenc, Meritxell Bellet- Ezquerra, Manuel Ruíz - Borrego, Miguel Gil-Gil, Peter Schmid, Charles M. Perou, Joel S. Parker, Patricia Villagrasa, Ana Vivancos, Aleix Prat, Antonio Llombart-Cussac. ctDNA-based DNADX in hormone receptor-positive and HER2-negative (HR+/HER2-) advanced breast cancer following endocrine therapy and CDK4/6 inhibition: a correlative analysis from the randomized phase 2 PARSIFAL trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-15-06.
Abstract Background: Abemaciclib is an orally administered inhibitor of cyclin-dependent kinase (CDK) 4/6, dosed twice daily (BID) on a continuous schedule. Diarrhea is a frequently associated adverse event. It is predictable and manageable with antidiarrheal medication, typically occurs within the first month of therapy, and decreases over the duration of treatment. In the MONARCH 1, 2, and 3 studies, Grade 3 diarrhea was experienced by 9% to 20% of patients (pts) receiving abemaciclib. Study design/Objectives: Study I3Y-MC-JPCP (ClinicalTrials.gov, NCT03703466) was a multicenter, randomized, open-label phase 2 study designed to evaluate the impact of food on the incidence of Grade 3 or prolonged Grade 2 diarrhea in HR+, HER2− metastatic breast cancer (mBC) pts receiving abemaciclib monotherapy 200 mg orally BID during the first 3 cycles of study treatment. Methods: Pts with HR+, HER2− mBC and ECOG performance status ≤1 who had progressed after prior anti-estrogen therapy for mBC and received prior treatment with ≥1 chemotherapy regimen for mBC, but were CDK4/6i naive, were randomly assigned 1:1:1 to receive abemaciclib with a meal, in a modified fasted condition (defined as ≥1 h before or ≥2 h after a meal), or without regard to food. Primary study endpoints were the incidence of ≥Grade 3 diarrhea; incidence of Grade 2 diarrhea lasting >7 days; dose reductions, dose interruptions, and treatment discontinuations due to diarrhea; and use of antidiarrheal agents. Secondary endpoints included overall safety and pharmacokinetic analysis. A pt-held electronic diary was used to record daily information on number of stools, diarrhea, loperamide use, and timing of abemaciclib intake relative to meals. Compliance with diary completion was centrally monitored. Multicenter training and implementation of e-diaries used a variety of paper and electronic resources tailored to end user (research staff, site staff, patient). Physicians had real-time access to data enabling accurate assessment of diarrhea. Results: This study randomized 72 pts in five countries from December 2018 to April 2019; 71 pts (median age 56.0 y) were treated with abemaciclib in one of three study arms: with a meal (Arm 1, n=24), modified fasted condition (Arm 2, n=23) and without regard to food (Arm 3, n=24). Mean compliance for e-diary completion was 95.7% for the overall population. Mean compliance with meal conditions was 99.5% in Arm 1 and 95.2% in Arm 2 (not applicable for Arm 3). In Arms 1, 2 and 3, 83.3%, 78.3% and 91.7% of pts received ≥3 cycles, respectively. Primary endpoints during the first three treatment cycles are summarized (Table). Table 1Arm 1 (n=24)Arm 2 (n=23)Arm 3 (n=24)Overall (n=71)≥1 Grade 2 diarrhea lasting >7 days, %8.317.420.815.5≥1 Grade 3 diarrhea, %4.2*001.4≥1 Grade 4 diarrhea, %0000≥1 Dose reduction due to diarrhea, %16.78.712.512.7≥1 Dose interruption due to diarrhea, %16.74.38.39.9Treatment discontinued due to diarrhea, %0000Loperamide use, %95.891.395.894.4* Duration of Grade 3 diarrhea was 1 day. This study was descriptive and not powered to analyze differences between study arms. Overall, the most frequently reported Grade 3/4 treatment-emergent adverse events related to treatment were neutropenia (28.2%), leukopenia (11.3%), thrombocytopenia (7.0%), fatigue (5.6%), nausea (5.6%) and lymphopenia (5.6%). Details on patient-reported diarrhea incidence and management, and PK analyses will be presented at conference. Conclusions: Global compliance with e-diary completion and meal condition was >95%. Diarrhea at high grade occurred at much lower incidence than previously reported (1.4% overall) and was of short duration (1 day). Diarrhea was predominantly low grade and managed with loperamide and dose modifications in all meal cohorts. Citation Format: Elgene Lim, Frances Boyle, Meena Okera, Sherene Loi, Sema Sezgin Goksu, Gertjan van Hal, Daisy G Hartman, Jonathon Colby Gable, Gregory L Price, Anwar Hossain, M C Gainford, Meritxell Bellet Ezquerra. The impact of food on tolerability of abemaciclib in patients with previously treated hormone receptor-positive, HER2-negative, metastatic breast cancer: An open-label, randomized phase 2 study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-14-05.
Abstract Background: Obesity has been associated with worse pathological complete response (pCR) to neoadjuvant chemotherapy (NACT) and overall outcome in breast cancer patients (pts). Our aim was to retrospectively evaluate body mass index (BMI) as a predictive factor of pCR to NACT in pts treated at our institution, taking into account tumor HER2 status and CT dose adjustment. Pts and methods: Pts with invasive breast cancer who received NACT followed by surgery at Vall d'Hebron University Hospital from January 2004 to December 2008 were analyzed. Pts were categorized as normal/underweight (BMI < 25 kg/m2), overweight (BMI of 25 to < 30 kg/m2), and obese (BMI ≥30 kg/m2). The overweight and obese groups were combined (BMI-high) and then compared with the normal/underweight group. Univariate and multivariate analyses were performed to assess the association between BMI and pCR (no invasive tumor in breast and nodes). Results: 256 consecutive pts were included. Median age was 52.5 years. According to BMI, 38.7% were normal/underweight and 59.4% were BMI-high. 23.4% of the pts had HER2 positive tumors (n=60), 84% received anthracyclines-and taxanes-based CT, and 46.6% of the HER2 positive pts were treated with trastuzumab. Drug dose was reduced in only five pts with a body surface area > 2m2. No statistically significant association was found between BMI and any tumor characteristics. In the univariate analysis, BMI-high was associated with worse pCR in the whole population (p=0.017), as well as in HER2 positive pts (p=0.013). In the multivariate analysis, BMI did not significantly predict pCR in the total population, although a trend was observed (p=0.098). In the HER2 positive subgroup, however, BMI was an independent predictive factor of pCR (p=0.001). Among luminal A [estrogen receptor positive and/or progesterone receptor positive and (Ki67 < 20% and histological grade 1 or 2)], luminal B [estrogen receptor positive and/or progesterone receptor positive and (Ki67 ≥20% or histological grade 3)], and triple negative tumors, BMI was not a predictive factor of pCR. Conclusions: Our results suggest that higher BMI is likely associated with worse pCR, particularly in HER2 positive pts. A better understanding of the molecular links between obesity and breast cancer is necessary to identify new predictive factors of pCR to NACT. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-03-04.
Abstract Purpose: Abemaciclib, a CDK4 & 6 inhibitor, is indicated for advanced breast cancer treatment. Diarrhea is a frequently associated adverse event of abemaciclib. The study objective was to investigate if food intake impacts local gastrointestinal toxicity.Methods: This Phase 2 study (I3Y-MC-JPCP, NCT03703466) randomized 72 patients 1:1:1 to receive abemaciclib 200mg monotherapy twice daily (1) with a meal, (2) in a modified fasting state or (3) without regard to food. Primary endpoints included: incidence of investigator assessed severe (≥Grade 3), prolonged (>7-days) Grade 2 diarrhea, treatment discontinuation, dose modifications, and loperamide utilization during the first 3 cycles of treatment. Patient outcomes were captured via a daily electronic diary. Pharmacokinetics (PK) are reported.Results: Median duration of Grade 3 diarrhea was 1 day by both investigator assessment (1 patient in Arm 1) and patient-reported assessment (1 patient each in Arms 1 and 3). Median duration of investigator-assessed Grade 2 diarrhea was 2 days overall. Ninety-four percent of patients used loperamide at least once. Abemaciclib PK was comparable across the 3 arms. Conclusion: Diarrhea incidence associated with abemaciclib was unrelated to timing of food intake, was predominantly low grade, of short duration and well managed with loperamide and dose modifications.
Although the metastasic breast cancer is still an incurable disease, recent advances have increased significantly the time to progression and the overall survival. However, too much information has been produced in the last 2 years, so a well-based guideline is a valuable document in treatment decision making. The SEOM guidelines are intended to make evidence-based recommendations on how to manage patients with advanced and recurrent breast cancer to achieve the best patient outcomes based on a rational use of the currently available therapies. To assign a level of certainty and a grade of recommendation the United States Preventive Services Task Force guidelines methodology was selected as reference.
Transaminase elevations are a known adverse event (AE) of special interest with RIB + ET. Understanding the incidence, duration, and management of these AEs is critical for maximizing treatment benefit with RIB + ET. We present a descriptive analysis of liver enzyme elevations with RIB + ET across multiple trials. Data from phase III registrational and phase IIIb expanded population (representative of real-world) trials were evaluated, including pts with HR+/HER2− advanced BC treated with RIB 600 mg + ET in MONALEESA (ML)-2, -3, and -7 and COMPLEEMENT-1, and pts from NATALEE with HR+/HER2− early BC treated with RIB 400 mg + ET. Incidence, time to onset, duration, and management of liver enzyme elevations were evaluated across each trial. With RIB + ET, the rates of all-grade (G) alanine aminotransferase (ALT) and aspartate aminotransferase (AST) elevations ranged from 13% to 19%; events were mostly G1/2 (Table). ALT/AST elevations were identified by recommended monitoring (serial liver function tests) and occurred early in RIB treatment. Among pts with G≥3 events, median time to onset ranged from 2.6 to 4.9 mo for each trial and median duration ranged from 0.7 to 1.6 mo; these events resolved with the current dose modification guidelines. Cases of Hy's law occurred in ≤1% of pts and were effectively managed by discontinuing RIB; most cases (95%) were resolved or resolving within 2.1 to 17.5 mo of RIB discontinuation. Discontinuation of RIB due to ALT/AST elevations was consistent across trials and occurred in ≤7% of pts. A similar incidence of liver events across trials at both the RIB 600- and RIB 400-mg doses suggests that dose does not play a key causative role in these AEs. Overall, cases of liver enzyme elevation were generally low grade and manageable with recommended dose modification guidance; severe cases were rare and reversible after discontinuation of RIB.Table: 277Pn (%)ML-2 N=334ML-3 N=483ML-7 N=335NATALEE N=2525COMPLEEMENT-1 N=3246ALT elevationAll G52 (16)70 (14)43 (13)492 (19)526 (16)G3/431 (9)41 (8)18 (5)192 (8)249 (8)aAST elevationAll G50 (15)64 (13)40 (12)426 (17)459 (14)G3/419 (6)29 (6)12 (4)118 (5)184 (6)aHy's law4 (1)2 (<1)08 (<1)7 (<1)Discontinuation due to:ALT increased15 (4)22 (5)8 (2)180 (7)197 (6)AST increased9 (3)13 (3)5 (1)71 (3)129 (4)Dose interruption due to:ALT increased17 (5)38 (8)16 (5)255 (10)245 (8)AST increased12 (4)37 (8)11 (3)171 (7)209 (6)Dose adjustment due to:ALT increased10 (3)5 (1)5 (1)49 (2)50 (2)AST increased5 (1)6 (1)4 (1)16 (1)Not reportedaData reported as Grade ≥3. Open table in a new tab
Abstract INTRODUCTION AND OBJECTIVES Palbociclib associated with hormone therapy (HT) has shown significant benefit in progression-free survival (PFS) and response rate versus HT alone in patients with HR+, HER2- MBC. The PALBOSPAIN study evaluates the efficacy and safety of palbociclib treatment under real-life conditions. The main objective of the study was to assess PFS, and secondary objectives were overall survival (OS), response rate, time to next line of treatment, percentage of dose reduction and safety. MATERIAL AND METHODS This is an observational, ambispective, multicenter, nation-wide study. Patients diagnosed with HR+/HER2- MBC who had started first-line treatment with palbociclib between November 2017 and November 2019 were included. Patients treated within a clinical trial were excluded, as were those who had received any previous systemic treatment for advanced disease. RESULTS 762 patients from 35 centers were included. 79% (n=600) were postmenopausal, 54.9% (n=418) had visceral disease, and 30.6% (n=233) had de-novo metastatic disease. Palbocliclib was combined with an aromatase inhibitor in 69.6% of patients and fulvestrant in 30.2% Four groups were established to assess efficacy (table 1): overall population; patients with de-novo metastatic disease (cohort A); patients relapsing >12 months after the end of adjuvant hormonal therapy (cohort B); and patients relapsing within 12 months after the end of adjuvant hormonal therapy (cohort C). Median PFS was 24 months (CI 95%; 25-27) overall and 28 (IC 95%; 23-39), 29 (IC 95%;25-35) and 14 months (IC 95%;11-17) for cohorts a, B and C, respectively. Median overall survival was 42 months (40-NA). The most common side effects were neutropenia (71.3%, grade 3-4 in 52.5%, no episodes of febrile neutropenia), fatigue (38.6%), leucopenia (29.8%), anemia (28.9%), articular pain (19%), and thrombocytopenia (2,2%). 49% (n=385) of patients required dose reduction of palbociclib (one level in 27.6% and two levels in 21.4%). CONCLUSION In the first two years after its approval in Spain, palbociclib in first line of HR+/HER2- MBC in real-life conditions yielded PFS and safety results comparable to those of PALOMA 2 and PALOMA 3 clinical trials. OS results were poorer, although the population included in this retrospective study is heterogeneous and median survival values have not been reached in some subgroups. Table 1. Efficay results of palbociclib in real world Citation Format: Noelia Martínez-Jáñez, Meritxell Bellet Ezquerra, Fernando Henao, Luis Manso, Antonio Antón, Pilar Zamora, Serafin Morales Murillo, Pablo Tolosa, Raquel Andrés, Lourdes Calvo, Elena Galve, Rafael Lopez, Francisco Ayala de la Peña, Sara López-Tarruella, Laia Boronat, Tamara Martos, J. Ignacio Chacón, Isabel Álvarez, Juan de la Haba-Rodríguez, Fernando Moreno Antón. PALBOSPAIN: OBSERVATIONAL ANALYSIS OF FIRST-LINE THERAPY WITH PALBOCICLIB IN PATIENTS WITH HR+/HER2- METASTATIC BREAST CANCER (MBC) IN REAL-LIFE CONDITIONS [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-01-28.
Abstract Background. The phase 3 PALLAS trial (NCT02513394) compared two years of the CDK4/6 inhibitor palbociclib with endocrine therapy of provider choice, versus endocrine therapy alone, as adjuvant treatment for patients with Stage II-III hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer. Genomic subtype (PAM50 intrinsic subtype) measured from whole-transcriptome RNA sequencing data was defined in the protocol of the PALLAS trial as the primary biomarker for analysis of prediction and prognosis. Clinical data have been previously presented (Gnant et al, JCO 2022), and the trial now has 5-year median follow-up. Methods. As part of trial eligibility, all participants in PALLAS provided a tumor tissue block prior to randomization (surgical if primary resection, core biopsy if neoadjuvant treatment) for translational analyses (TRANS-PALLAS). The biorepository and laboratory were blinded to identity and processed samples in random order, to minimize bias. Nucleic acids were extracted from samples with sufficient tumor tissue and cellularity (>25 mm2 with ≥20% cancer nuclei). The Genome Sequencing Center at Washington University St. Louis performed whole-transcriptome RNA sequencing. Libraries were prepared from 1 µg DNase-1 treated total RNA, if total RNA DV200 >28 (Agilent Bioanalyzer), using an unbiased library protocol of RNA HyperPrep kit with RiboErase (HMR) (Kapa Biosystems, Wilmington, MA). 100 bp paired-end sequencing was performed on NovaSeq 6000 using S4 Reagent Kit (Illumina, San Diego, CA), with 48 libraries pooled per lane. Intrinsic subtype was determined using Bioclassifier package (Research PAM50 script, Parker et al.) only for the analysis population of primary breast cancer samples that had not been exposed to prior neoadjuvant therapy. Invasive disease-free survival (IDFS) will be visualized using Kaplan-Meier plots, with log-rank test between groups. Cox models of proportional hazards will be developed to evaluate prognosis adjusted for known clinical covariates, or for predictive interactions. The pre-defined level of significance is a two-sided 0.05. Results. From the total study population of 5796 enrolled patients, 4655 tissue blocks had sufficient tumor content to process for RNA, with 3931 yielding sufficient RNA for sequencing, and 2669/4655 (57.3%) submitted tissue blocks had DV200 ≥28 and were successfully sequenced. Clinical unblinding revealed 2370 unique patients (1182 in the palbociclib treatment arm and 1188 in the control arm) with intrinsic subtype defined from their untreated primary tumor: 1555 (65.6%) luminal A, 287 (12.1%) luminal B, 167 (7.0%) HER2-enriched, 310 (13.1%) basal-like, 51 (2.2%) normal-like. We will report the results for association of molecular subtype, proliferation score, and Risk of Recurrence (ROR) scores with invasive disease-free survival (IDFS) by treatment arm at the meeting. Conclusions. The TRANS-PALLAS cohort represents one of the largest biorepositories of HR+/HER2- early breast cancer reflecting contemporary systemic management in the framework of a prospectively randomized global trial. Required tumor block submission in this phase 3 trial yielded data from unbiased whole-transcriptome RNA sequencing of the primary tumor prior to treatment from 41% of the PALLAS participants. The proportion of luminal A cancers was unexpectedly high (66%), indicating a lower-risk distribution of cancers in this population. The planned analyses of prediction and prognosis are ongoing and those results will be presented at the time of the meeting. Support: AFT, ABCSG, Pfizer, ECOG-ACRIN, NSABP Foundation, GBG, BIG; Clinicaltrials.gov Identifier: NCT02513394; https://acknowledgments.alliancefound.org Citation Format: Daniel Stover, Dominik Hlauschek, Erica Mayer, W. Fraser Symmans, Mark Watson, Iros Barozzi, Martin Filipits, Karla Ballman, Meritxell Bellet- Ezquerra, Justin Balko, Gabor Rubovszky, Nicholas Zdenkowski, Adam Brufsky, Guenther Steger, Claudine Isaacs, Sibylle Loibl, Fernando Henao, Meredith Regan, Yuan Liu, Christian Fesl, Patrick O'Brien, Angela DeMichele, Michael Gnant, Otto Metzger. Protocol-defined biomarker analysis in the PALLAS (AFT-05) adjuvant trial: Genomic subtype derived from RNA sequencing of HR+/HER2- early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-07.
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