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Abstract Background Full RNA-Seq is a fundamental research tool for whole transcriptome analysis. However, it is too costly and time consuming to be used in routine clinical practice. We evaluated the transcript quantification agreement between RNA-Seq and a digital multiplexed gene expression platform, and the subtype call after running the PAM50 assay in a series of breast cancer patients classified as triple negative by IHC/FISH. The goal of this study is to analyze the concordance between both expression platforms overall, and for calling PAM50 triple negative breast cancer intrinsic subtypes in particular. Results The analyses were performed in paraffin-embedded tissues from 96 patients recruited in a multicenter, prospective, non-randomized neoadjuvant triple negative breast cancer trial (NCT01560663). Pre-treatment core biopsies were obtained following clinical practice guidelines and conserved as FFPE for further RNA extraction. PAM50 was performed on both digital multiplexed gene expression and RNA-Seq platforms. Subtype assignment was based on the nearest centroid classification following this procedure for both platforms and it was concordant on 96% of the cases (N = 96). In four cases, digital multiplexed gene expression analysis and RNA-Seq were discordant. The Spearman correlation to each of the centroids and the risk of recurrence were above 0.89 in both platforms while the agreement on Proliferation Score reached up to 0.97. In addition, 82% of the individual PAM50 genes showed a correlation coefficient > 0.80. Conclusions In our analysis, the subtype calling in most of the samples was concordant in both platforms and the potential discordances had reduced clinical implications in terms of prognosis. If speed and cost are the main driving forces then the preferred technique is the digital multiplexed platform, while if whole genome patterns and subtype are the driving forces, then RNA-Seq is the preferred method.

HER2-positive metastatic breast cancer is an aggressive disease with a limited number of treatment options. In the last 15 years, new drugs such as trastuzumab, pertuzumab, lapatinib or trastuzumab emtansine (TDM-1) have sprouted for these patients. There is a huge lack of evidence on the use of some of these drugs in patients with chronic renal failure, who need hemodialysis. We have reviewed the use of TDM-1 in these type of patients in the literature with unsuccessful results.In this article we want to present a case report to illustrate the safety and efficacy of TDM-1 in a patient on hemodialysis.

Abstract Goals of endocrine therapy for advanced breast cancer (ABC) include prolonging survival rates, maintaining the quality of life, and delaying the initiation of chemotherapy. We evaluated the effectiveness of fulvestrant as first-line in patients with estrogen receptor (ER)-positive ABC with relapse during or after adjuvant anti-estrogenic therapy in real-world settings. Retrospective, observational study involving 171 postmenopausal women with ER-positive ABC who received fulvestrant as first-line between January 2011 and May 2018 in Spanish hospitals. With a median follow-up of 31.4 months, the progression-free survival (PFS) with fulvestrant was 14.6 months. No differences were seen in the visceral metastatic (14.3 months) versus non-visceral (14.6 months) metastatic subgroup for PFS. Overall response rate and clinical benefit rate were 35.2% and 82.8%. Overall survival was 43.1 months. The duration of the clinical benefit was 19.2 months. Patients with ECOG performance status 0 at the start of treatment showed a significant greater clinical benefit rate and overall survival than with ECOG 1–2. Results in real-world settings are in concordance with randomized clinical trials. Fulvestrant continues to demonstrate clinical benefits in real-world settings and appears be well tolerated as first-line for the treatment of postmenopausal women with ER-positive ABC.

Background: Concomitant intake of proton pump inhibitors (PPIs) may create drug-drug interactions, potentially impacting efficacy of anticancer agents. In the phase III PALLAS trial, the addition of palbociclib capsules to standard adjuvant endocrine therapy in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer did not improve invasive disease-free survival (iDFS). We explored whether concomitant use of PPIs affected survival outcomes in patients treated with palbociclib in PALLAS., Methods: This is an exploratory analysis of PALLAS including patients who received at least one dose of palbociclib capsules. We aimed to determine the association of concomitant PPI use with iDFS, distant relapse-free survival and overall survival. Uni- and multivariable Cox models with time-dependent PPI were used. The association between PPI use and neutropenia was also investigated., Results: Of 2840 patients treated with palbociclib + endocrine therapy, 525 (18.5%) had concomitant PPI and palbociclib intake. PPI intake was significantly associated with older age, post-menopausal status, use of aromatase inhibitors, higher body mass index, and worse Eastern Cooperative Oncology Group status (all P < 0.001). Concomitant PPI intake was not significantly associated with survival outcomes (iDFS, distant relapse-free survival, overall survival). All-grade neutropenia rates were numerically lower in patients who initiated a PPI before study start compared with patients never initiating PPIs (adjusted odds ratio 0.81, 95% confidence interval 0.60-1.09)., Conclusions: Our exploratory analysis did not demonstrate worse survival outcomes in patients receiving concomitant palbociclib and PPIs in PALLAS. Nonetheless, careful consideration of possible drug-drug interactions is important, especially when studying novel agents in the early breast cancer setting., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Complete pathological response to neoadjuvant treatment (NAT) in breast cancer is associated with prolonged survival. Compared to other breast cancer immunophenotypes, luminal tumors are the least chemosensitive with low rates of pathological response within this molecular subtype. Thus, finding predictors of response in this subset remains challenging. The emerging concept of low human epidermal growth factor receptor 2 (HER2) expression has led to a repurpose of the current prognostic system. Little is known about its correlation with response to NAT., Objectives: This study aims to evaluate predictors of response in early-stage luminal breast cancer receiving neoadjuvant chemotherapy., Design: A total of 252 luminal patients who received NAT were retrospectively assessed in this cohort study., Methods: We analyzed the correlation of ki67 and HER2 low expression with the rate of pathologic response. Using ki67 as a continuous variable and applying the receiver operating characteristic curves method., Results: We identified that in patients with a ki67 expression level >37%, the probability of having a complete pathological response was 4.80 times higher (odds ratio = 4.80, 95% confidence interval: 1.92-12.04). In Her2-low breast cancer patients, Her2 expression did not correlate with a better response rate., Conclusion: In our study, a ki67 expression value greater than 37% constitutes a predictive biomarker of pathological complete response in the subgroup of patients with luminal B tumors and could be considered, therefore, an indicator for treatment decisions in this subgroup., Competing Interests: M.B.: Ipsen, Novartis, Pfizer, Roche (C/A, H); M.R.-B.: Pfizer, Novartis, Daichi, Pierre Fabre (C/A), Novartis, Pfizer, AstraZeneca, Eisai, Roche (H); A.F.: Roche, Pfizer, Novartis, Lilly, Seagen, Grunenthal (H), Roche, Pfizer, Novartis, Seagen (C/A); J.S.-B.: Pfizer, Novartis, Daichi, Pierre Fabre, Lilly (C/A), Novartis, Pfizer, AstraZeneca, Eisai, Roche, and Lilly (H). The other authors indicated no financial relationships., (© The Author(s), 2024.)

Background: The effect of the addition of cyclin-dependent kinases 4 and 6 inhibitors to endocrine therapy in terms of molecular downstaging remains undetermined. Switching from a high-risk to a low risk Recurrence Score (RS) group could provide useful information to identify patients who might not require chemotherapy. The purpose of this study was to assess the biological and clinical activity of letrozole plus palbociclib as neoadjuvant treatment for patients with hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative early breast cancer with an initial Oncotype DX RS ≥18., Patients and Methods: Participants were women aged ≥18 years with HR-positive/HER2-negative, Ki67 ≥ 20%, stage II-IIIB early breast cancer with a baseline RS ≥18. Eligible patients with a pretreatment RS 18-25 (cohort A) and 26-100 (cohort B) received six 28-day cycles of letrozole (2.5 mg per day; plus goserelin if pre- or perimenopausal) plus palbociclib (125 mg per day; 3/1 schedule) before surgery. The primary endpoint for both cohorts was the proportion of patients who achieved an RS ≤25 at surgery or a pathological complete response (pCR)., Results: A total of 67 patients were enrolled, among which 65 were assessable for the primary endpoint (32 patients in cohort A and 33 in cohort B). At surgery, 22 (68.8%) patients in cohort A and 18 (54.5%) patients in cohort B had an RS ≤25 or a pCR [only 1 (3.0%) patient in cohort B], meeting the primary endpoint in cohort B (P < 0.01), but not in cohort A (P = 0.98). No new safety signals were identified., Conclusions: The efficacy of neoadjuvant treatment with letrozole plus palbociclib does not seem to depend on pretreatment RS for patients with RS ≥18. However, around half of patients with HR-positive/HER2-negative early breast cancer with an RS 26-100 at baseline achieved molecular downstaging with this regimen., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Trastuzumab deruxtecan (T-DXd) is approved for human epidermal growth factor receptor 2 (HER2)-positive and HER2-low advanced breast cancer (ABC). T-DXd has shown encouraging intracranial activity in HER2-positive ABC patients with stable or active brain metastases (BMs); however, its efficacy in patients with HER2-low ABC with BMs is not well established yet., Methods: DEBBRAH is a single-arm, five-cohort, phase II study evaluating T-DXd in patients with central nervous system involvement from HER2-positive and HER2-low ABC. Here, we report results from patients with heavily pretreated HER2-low ABC and active BMs, enrolled in cohorts 2 (n = 6, asymptomatic untreated BMs) and 4 (n = 6, progressing BMs after local therapy). Patients received 5.4 mg/kg T-DXd intravenously once every 21 days. The primary endpoint was intracranial objective response rate per Response Assessment in Neuro-Oncology Brain Metastases (RANO-BM) for both cohorts., Results: Intracranial objective response rate per RANO-BM was 50.0% [3/6 patients; 95% confidence interval (CI) 11.8% to 88.2%] and 33.3% [2/6 patients; 95% CI 4.3% to 77.7%; P = 0.033 (one-sided)] in cohorts 2 and 4, respectively. All responders had partial responses. Median time to intracranial response was 2.3 months (range, 1.5-4.0 months) and median duration of intracranial response was 7.2 months (range, 2.8-16.8 months). Median progression-free survival per RECIST v.1.1. was 5.4 months (95% CI 4.1-10.0 months). Treatment-emergent adverse events occurred in all patients included (16.7% grade 3). Three patients (25.0%) had grade 1 interstitial lung disease/pneumonitis., Conclusions: T-DXd demonstrated promising intracranial activity in pretreated HER2-low ABC patients with active BMs. Further studies are needed to validate these results in larger cohorts. This trial is registered with ClinicalTrials.gov, NCT04420598., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: The capsule formulation of CDK4/6 inhibitor palbociclib has reduced solubility at gastric pH > 4.5 and may have decreased activity when used with proton-pump inhibitors (PPI). Herein, we report the effect of PPI on palbociclib capsule activity and safety in the PARSIFAL study., Methods: First-line endocrine-sensitive, hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC) patients received palbociclib capsules plus fulvestrant or letrozole. The primary endpoint was progression-free survival (PFS). This post-hoc analysis compared PPI use. Patients were PPI-naïve (N-PPI) if not on PPI during the study, and either early (E-PPI) or long-term PPI (LT-PPI) if on PPI at study entry or for at least ≥⅔ of treatment, respectively. PPI groups were not mutually exclusive., Results: Among 486 patients, 66.9 % were N-PPI, 13.2 % E-PPI, 18.7 % LT-PPI, and 11.5 % of the PPI users were defined as neither. Median PFS (mPFS) was 29.6 months in the study population, 28.7 months in N-PPI, 23.0 months in E-PPI (Hazard Ratio [HR] 1.5; 95%Confidence Interval [CI] 1.1-2.2; p = 0.024), and 23.0 months in LT-PPI (HR 1.4; 95%CI 1.0-1.9; p = 0.035). By landmark analysis, PPI use was associated with poorer mPFS at 3 and 12 months. Grade ≥3 hematological adverse events occurred in 71.7 % of N-PPI, 57.8 % of E-PPI (p = 0.021), and 54.9 % of LT-PPI (p = 0.003). Dose reductions and dosing delays due to hematological toxicity occurred in 70.8 % of N-PPI, 56.3 % of E-PPI (p = 0.018), and 52.7 % of LT-PPI (p = 0.002)., Conclusions: PPI use may reduce palbociclib capsule toxicity, dose modifications, and clinical activity in HR+/HER2- ABC., Competing Interests: Declaration of competing interest SDC reports consulting for MEDSIR and IQVIA and honoraria from Pierre-Fabre, Novartis, and AstraZeneca. JMPG reports consulting for Roche, Eiasi, Daichii Sankyo, AstraZeneca, Gilead, MSD and Seagen and travel expenses from Roche. MB reports consulting fees from Pfizer, Novartis, Lilly, and Steamline-Menarini; honoraria from Pfizer, Novartis, and Lilly; and trave support from Pfizer. FD reports travel grants for Daichii, Novartis, and Pfizer, and participation in monitor/advisory boards for Daiichi, Seagen, Novartis, Gilead, Lilly, and MSD. MGG reports honoraria from Pfizer, Novartis, and AstraZeneca, travel grants from Lilly, Daiichi-Sankyo, and Pfizer, and participation in monitoring/advisory boards for AstraZeneca, Seagen, and Gilead. MRB reports honoraria from Pfizer, Novartis, AstraZenca, and Daiichi Sankyo. JG reports consulting fees from Novartis, Pfizer, AstraZeneca; honoraria from Novartis; and travel support from Roche and AstraZeneca. EAO reports consulting for AstraZeneca, Daichii, Gilead, MSD, and Seagen; honoraria from AstraZeneca, Daichii, Lilly, MSD, and Seagen; travel support from Daichii, Lilly, Gilead, and AstraZeneca; and participation in monitor/advisory boards for Gilead, AstraZeneca, Seagen, and Dachii. PS reports honoraria from Pfizer, AstraZeneca, Novartis, Roche, Merck, and Boehringer Ingelheim; a consulting role for Pfizer, AstraZeneca, Novartis, Roche, Merck, Boehringer Ingelheim, Bayer, Eisai, Celgene, and Puma; and institutional grants from Roche, Genentech, Oncogenex, and Novartis. FM reports grants from Roche, Novartis, AstraZeneca, GSK, MSD, Clovis, Vaccibody, Gilead Sciences, and Esai; consulting fees from AstraZeneca, GSK, and Roche; honoraria from AstraZeneca, MSD, Lilly, Pfizer, Novartis, GSK, Clovis, Myriad, Daiich Sankyo, Seagen, Pierre-Fabre, and Agendia; travel support from AstraZeneca, GSK, Pfizer, and Roche; and participation in advisory boards for Palleos and Amgen. JG reports grant/research support from Roche, Eiasi, and Exact Science; honoraria or consultation fees from AstraZeneca, Daiichi, Eisai, Exact Science, Evapharm, GE Healthcare, Gilead, Lilly, MSD, Novartis, Pfizer, Pierre Fabre, Roche, Seagen, Sothema and participation in company sponsored speaker's bureaus for Exact Science, Lilly, and Novartis. AS reports grants from Celgene, Roche, Abbvie; travel grants from Celgene, Roche, Pfizer, AstraZeneca, and honoraria from Roche, Celgene, Pfizer, AstraZeneca, Novartis, MSD, Tesaro, Lilly, Seagen, Gilead, GSK, Bayer, Amgen, Pierre Fabre. JA reports trial funding from MEDSIR and consulting for Pfizer, Lilly, and Novartis. PZ reports honoraria from Pfizer, Novartis, Roche, and Pierre Fabre; and travel support from Pfizer, Novartis, Roche, and Lilly. DW reports honoraria from Pfizer, Novartis, AstraZeneca and travel grants from Roche, and Novartis. JC reports consulting for Roche, Celgene, Cellestia, AstraZeneca, Seattle Genetics, Daiichi Sankyo, Erytech, Athenex, Polyphor, Lilly, Merck Sharp&Dohme, GSK, Leuko, Bioasis, Clovis Oncology, Boehringer Ingelheim, Ellipses, Hibercell, BioInvent, Gemoab, Gilead, Menarini, Zymeworks, Reveal Genomics, Expres2ion Biotechnologies; honoraria from Roche, Novartis, Celgene, Eisai, Pfizer, Samsung Bioepis, Lilly, Merck Sharp&Dohme, Daiichi Sankyo.; research funding to the Institution from Roche, Ariad pharmaceuticals, AstraZeneca, Baxalta GMBH/Servier Affaires, Bayer healthcare, Eisai, F. Hoffman-La Roche, Guardanth health, Merck Sharp&Dohme, Pfizer, Piqur Therapeutics, Puma C, Queen Mary University of London; stock shares for MEDSIR, Nektar Pharmaceuticals, Leuko (relative); Travel, accommodation, expenses from Roche, Novartis, Eisai, Pfizer, Daiichi Sankyo, Astrazeneca, Gilead; and Patents: Pharmaceutical Combinations of A Pi3k Inhibitor And A Microtubule Destabilizing Agent. Javier Cortés Castán, Alejandro Piris Giménez, Violeta Serra Elizalde. WO 2014/199294 A. ISSUED Her2 as a predictor of response to dual HER2 blockade in the absence of cytotoxic therapy. Aleix Prat, Antonio Llombart, Javier Cortés. US 2019/0338368 A1. LICENSED. ALC reports research support from Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Gilead, and Daichii-Sanyo; consulting for Lilly, Roche, Pfizer, and Novartis; participation in speakers' bureaus for Lilly, AstraZeneca, Merck Sharp & Dohme; travel support from Roche, Pfizer, AstraZeneca; and stock or other ownership in MEDSIR and Initia-Research. The remaining authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The PHERGain trial investigated the potential of metabolic imaging to identify candidates for chemotherapy deescalation in human epidermal growth factor receptor 2 (HER2)-positive, invasive, operable breast cancer with at least 1 breast lesion evaluable by [ 18 F]FDG PET/CT. [ 18 F]FDG PET/CT responders were defined as patients with an SUV max reduction (ΔSUV max ) of at least 40% in all of their target lesions after 2 cycles of trastuzumab and pertuzumab (HP) (with or without endocrine therapy). In total, 227 of 285 patients (80%) included in the HP arm showed a predefined metabolic response and received a total of 8 cycles of HP (with or without endocrine therapy). Pathologic complete response (pCR), defined as ypT0/isN0, was achieved in 37.9% of the patients. Here, we describe the secondary preplanned analysis of the best cutoff of ΔSUV max for pCR prediction. Methods: Receiver-operating-characteristic analysis was applied to look for the most appropriate ΔSUV max cutoff in HER2-positive early breast cancer patients treated exclusively with neoadjuvant HP (with or without endocrine therapy). Results: The ΔSUV max capability of predicting pCR in terms of the area under the receiver-operating-characteristic curve was 72.1% (95% CI, 65.1-79.2%). The optimal ΔSUV max cutoff was found to be 77.0%, with a 51.2% sensitivity and a 78.7% specificity. With this cutoff, 74 of 285 patients (26%) would be classified as metabolic responders, increasing the pCR rate from 37.9% (cutoff ≥ 40%) to 59.5% (44/74 patients) ( P < 0.01). With this optimized cutoff, 44 of 285 patients (15.4%) would avoid chemotherapy in either the neoadjuvant or the adjuvant setting compared with 86 of 285 patients (30.2%) using the original cutoff ( P < 0.001). Conclusion: In the PHERGain trial, an increased SUV max cutoff (≥77%) after 2 cycles of exclusive HP (with or without endocrine therapy) achieves a pCR in the range of the control arm with chemotherapy plus HP (59.5% vs. 57.7%, respectively), further identifying a subgroup of patients with HER2-addicted tumors. However, the original cutoff (≥40%) maximizes the number of patients who could avoid chemotherapy., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/ PIK3CA -mutated advanced breast cancer (ABC)., Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL [<5.6 mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140 mg/dL [5.6-7.8 mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively., Findings: 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P  < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P  = 0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2)., Interpretation: In HR+/HER2-/ PIK3CA -mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia., Funding: Novartis Pharmaceuticals., Competing Interests: ALC reports research support from Roche, Agendia, Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Gilead, and Daichii-Sanyo; a consulting or advisory role with Lilly, Roche, Pfizer, and Novartis. Speakers’ bureaus for Lilly, AstraZeneca, Merck Sharp & Dohme; travel support from Roche, Pfizer, AstraZeneca; and stock or other ownership in MEDSIR and Initia-Research. JMPG reports a consulting or advisory role with Lilly, Roche, Eisai, Daichii Sankyo, AstraZeneca, Seattle Genetics; and employment at MEDSIR. MRB reports research support and participating in an advisory board of Novartis. PT reports a consulting or advisory role with AstraZeneca, Daiichi-Sankyo, Novartis and Seagen. Speakers’ bureaus for Pfizer, Novartis, Lilly, AstraZeneca, Daiichi-Sankyo and Seagen. IB reports grants and research support to the Institution: AstraZeneca, Lilly, Pfizer and Roche; honoraria and advisor colaboration: AstraZeneca, Roche, Novartis, Eisai, Celgene, Pfizer, Lilly, Pierre-Fabre, Bristol-Myers Squibb, Daiichi Sankyo, Grünenthal, Seagen and Veracyte and support for attending meetings and/or travel: AstraZeneca, Roche, Novartis, Pfizer, Lilly, Pierre-Fabre, Bristol-Myers Squibb and Daiichi Sankyo. BR reports travel support from Roche and Lilly. AFO reports travel support from Novartis. CS reports research support, consulting or advisory role from Genentech, AstraZeneca, Aragon Pharmaceuticals, Bayer Pharma, Byondis, Boehringer Ingelheim, Bristol-Myers Squibb, Cytomx Therapeutics, Daiichi Sankyo, F. Hoffmann-La Roche, Eisai, Genomic Health, GlaxoSmithKline, Innoup Farma, Eli Lilly, Macrogenics, Menarini Ricerche, Merck Sharp & Dohme, Merus, Millennium Pharmaceuticals, Novartis, Pfizer, Pierre Fabre, PintPharma, Puma Biotechnology, Sanofi, Seattle Genetics, Zymeworks. JPL reports honoraria from Seagen, Novartis, Pfizer, AstraZeneca/Daiichi Sankyo, Eli Lilly, Roche; and a consulting or advisory role with Seagen, Novartis, AstraZeneca/Daiichi Sankyo, Roche. EL reports honoraria from Ipsen, MSD, Pfizer, AstraZeneca/Daiichi Sankyo and Roche. EG reports honoraria from Roche/Genentech, Pfizer, Novartis, AstraZeneca, Seagen; a consulting or advisory role with AstraZeneca, Seagen, PharmaMar, Gilead Sciences; and speakers’ bureaus for Pfizer, Novartis, Roche. SGS reports honoraria for speaking from Novartis and GSK; Advisory role from Lilly, Seagen and Astra Zeneca; and travel expenses from Clovis and Pfizer outside the submitted work. EC reports consultancy and speakers’ bureaus for Novartis, Pfizer, Roche, Lilly, Celgene; and personal fees from Novartis, Pfizer, Roche, Lilly, Celgene, during the conduct of the study. JFC reports honoraria from Roche, AstraZeneca, Teva, Celgene, Pfizer, GSK, Novartis; and a consulting or advisory role with Roche, AstraZeneca, Pfizer, GSK, Novartis. MSC reports advisory Board of MEDSIR, Optimapharm; Speaker's Bureau in MEDSIR, Optimapharm; and Funding from MEDSIR, Optimapharm, FGP has taken part in advisory panels for Sanofi and Novo Nordisk; has received research support from Sanofi, Novo Nordisk, Boehringer Ingelheim Pharmaceuticals and Lilly; and has acted as a speaker for Sanofi, Novo Nordisk, Boehringer Ingelheim Pharmaceuticals, AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Co. and Lilly. JC reports research support from ARIAD, Astrazeneca, Baxalta GMBH/Servier Affaires, Bayer, Eisai, Guardanth health, Merck Sharp & Dohme, Pfizer, Puma, Queen Mary University of London, Roche, Piqur; honoraria from Novartis, Eisai, Celgene, Pfizer, Roche, Samsung, Eli Lilly, Merck Sharp & Dohme Daiichi Sankyo; a consulting or advisory role with Celgene, Cellestia Biotech, AstraZeneca, Roche, Seattle Genetics, Daiichi Sankyo, ERYTECH Pharma, Polyphor, Athenex, Lilly, SERVIER, Merck Sharp & Dohme, GlaxoSmithKline, Leuko, Clovis Oncology, Bioasis, Boehringer Ingelheim, Ellipses Pharma, HiberCell, Bioinven, GEMoaB, Gilead Sciences, Menarini, Zymeworks, Reveal Genomics; stock or other ownership in Leuko, MEDSIR, Nektar; and travel support from Roche, Pfizer, Eisai, Novartis, Daiichi Sankyo. AU, EMD, SB, BB, MGC, PCC, AL, JLAR report no competing interests. JMPG, GM, PG, DAL, and MSC are employed by MEDSIR., (© 2024 Published by Elsevier Ltd.)

Background: Preclinical data suggest synergistic activity with the combination of programmed death-1 and cyclin-dependent kinase 4/6 blockade in oestrogen receptor-positive/human epidermal growth factor 2-negative (ER+/HER2-) breast cancer. The noncomparative phase 1b/2 CheckMate 7A8 study (NCT04075604) evaluated neoadjuvant treatment with nivolumab, palbociclib, and anastrozole in patients with ER+/HER2- breast cancer. Here, we report outcomes from the safety run-in phase., Methods: Patients with histologically confirmed, untreated ER+/HER2- breast cancer, primary tumour ≥2 cm, ECOG performance status ≤1, and eligible for post-treatment surgery received nivolumab 480 mg intravenously every 4 weeks, palbociclib 125 mg or 100 mg orally once daily for 3 weeks per cycle, and anastrozole 1 mg orally once daily for five 4-week cycles, or until disease progression. The primary endpoint was the proportion of patients with dose-limiting toxicities (DLTs) within 4 weeks of treatment initiation., Results: At safety data review, 21 patients were treated (palbociclib 125-mg group: n = 9; palbociclib 100-mg group: n = 12). DLTs were reported in 2 (22.2%) and 0 patients in the palbociclib 125-mg and 100-mg groups, respectively. Across both groups, 9 patients discontinued treatment due to toxicity (grade 3/4 hepatic adverse events [n = 6], grade 3 febrile neutropaenia [n = 1], grade 1 pneumonitis [n = 1], and grade 3 rash and grade 2 immune-mediated pneumonitis [n = 1]). Consequently, the study was closed early., Conclusions: Neoadjuvant treatment with nivolumab, palbociclib, and anastrozole showed a high incidence of grade 3/4 hepatotoxicity and treatment discontinuation, indicating that this combination should not be further pursued for treatment of primary ER+/HER2- breast cancer., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: G. Jerusalem declares acting in a consultancy or advisory role for AbbVie, Amgen, AstraZeneca, Bristol Myers Squibb, Daiichi Sankyo, Lilly, Novartis, Pfizer, Roche; receiving honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Lilly, Novartis, Pfizer, Roche, Seagen; research funding from Novartis, Pfizer, Roche; travel and accommodation expenses from Amgen, AstraZeneca, Bristol Myers Squibb, Lilly, Novartis, Pfizer, Roche; and medical writing support from Amgen, AstraZeneca, Bristol Myers Squibb, Lilly, Medimmune, Merck Sharp and Dohme Corp, Novartis, Roche. A. Prat declares acting in a consultancy or advisory role for AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, NanoString Technologies, Novartis, Oncolytics Biotech, Pfizer, Puma, Roche; receiving honoraria from Amgen, Daiichi Sankyo, Guardant Health, Lilly, Merck Sharp and Dohme Corp, Novartis, Pfizer, Roche; research funding from Incyte, Novartis, Puma, Roche; travel and accommodation expenses from Daiichi Sankyo; an employee of Novartis; and a stockholder of Reveal Genomics. R. Salgado declares acting in a consultancy or advisory role for Bristol Myers Squibb and Roche; and travel and accommodation expenses from Merck Sharp and Dohme Corp, Puma, and Roche. M. Reinisch declares acting in a consultancy or advisory role for Daiichi Sankyo, Somatex, and Roche; receiving honoraria from AstraZeneca, Daiichi Sankyo, Lilly, Merck Sharp and Dohme Corp, Novartis, Pfizer, Roche, Seagen, Somatex; and travel and accommodation expenses from Novartis and Pfizer. C. Saura declares acting in a consultancy or advisory role for AstraZeneca, Ax's Consulting, Byondis, Daiichi Sankyo, Eisai, Exact Sciences, Exeter, F. Hoffmann-La Roche Ltd., International Society for the Study and Exchange of evidence from Clinical research And Medical experience (ISSECAM), Medical Statistics Consulting, MediTech, Merck Sharp and Dohme Corp, Novartis, Pfizer, Philips, Pierre Fabre, PintPharma, Puma, Roche, Sanofi, Seagen, Zymeworks, and research funding from Aragon, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Byondis, CytomX, Daiichi Sankyo, F. Hoffmann-La Roche Ltd., Genentech, German Breast Group Forchungs, GlaxoSmithKline, Immunomedics, Innoup, International Breast Cancer Study Group (IBCSG), Lilly, Macrogenics, Medica Scientia Innovation Research, Menarini Ricerche, Merck Sharp and Dohme Corp, Merus, Millennium, Novartis, Pfizer, Piqur, Puma, Roche, Sanofi, Seagen, Synthon, and Zenith. F. Ades, J. Filian, and N. Huang are employees and stockholders of Bristol Myers Squibb. A. Mazzei-Abba is an employee of Bristol Myers Squibb. S.M. Tolaney declares honoraria or consultation fees from 4D Pharma, AstraZeneca, Athenex, Blueprint Medicines, Bristol Myers Squibb, CytomX, Daiichi Sankyo, Eisai, Eli Lilly, Ellipses Pharma, Genentech/Roche, G1 Therapeutics, Gilead, Merck, Mersana Therapeutics, Novartis, Odonate, OncoPep, OncoSec, OncXerna, Pfizer, Puma, Reveal Genomics, Sanofi, Seagen, Zentalis, Zymeworks; presented at a public event organised by Chugai Pharma; and received grants/research supports from AstraZeneca, Bristol Myers Squibb, Certara, Cyclacel, Eisai, Eli Lilly, Exelixis, Genentech/Roche, Gilead, Merck, Nanostring, Nektar, Novartis, Odonate, Pfizer, Sanofi, and Seagen. M. Ruiz-Borrego and P. Nikolinakos have no conflicts of interest to disclose., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Prognostic and predictive biomarkers to cyclin-dependent kinases 4 and 6 inhibitors are lacking. Circulating tumor DNA (ctDNA) can be used to profile these patients and dynamic changes in ctDNA could be an early predictor of treatment efficacy. Here, we conducted plasma ctDNA profiling in patients from the PEARL trial comparing palbociclib+fulvestrant versus capecitabine to investigate associations between baseline genomic landscape and on-treatment ctDNA dynamics with treatment efficacy., Experimental Design: Correlative blood samples were collected at baseline [cycle 1-day 1 (C1D1)] and prior to treatment [cycle 1-day 15 (C1D15)]. Plasma ctDNA was sequenced with a custom error-corrected capture panel, with both univariate and multivariate Cox models used for treatment efficacy associations. A prespecified methodology measuring ctDNA changes in clonal mutations between C1D1 and C1D15 was used for the on-treatment ctDNA dynamic model., Results: 201 patients were profiled at baseline, with ctDNA detection associated with worse progression-free survival (PFS)/overall survival (OS). Detectable TP53 mutation showed worse PFS and OS in both treatment arms, even after restricting population to baseline ctDNA detection. ESR1 mutations were associated with worse OS overall, which was lost when restricting population to baseline ctDNA detection. PIK3CA mutations confer worse OS only to patients on the palbociclib+fulvestrant treatment arm. ctDNA dynamics analysis (n = 120) showed higher ctDNA suppression in the capecitabine arm. Patients without ctDNA suppression showed worse PFS in both treatment arms., Conclusions: We show impaired survival irrespective of endocrine or chemotherapy-based treatments for patients with hormone receptor-positive/HER2-negative metastatic breast cancer harboring plasma TP53 mutations. Early ctDNA suppression may provide treatment efficacy predictions. Further validation to fully demonstrate clinical utility of ctDNA dynamics is warranted., (©2023 The Authors; Published by the American Association for Cancer Research.)