115 research outputs found
SOPHIA : A phase 3, randomized study of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy in the treatment of patients with HER2+ metastatic breast cancer
No full textAbstract
Background: Despite significant advances in targeted therapy, HER2+ metastatic breast cancer (MBC) remains incurable. Ideal treatment includes pertuzumab and trastuzumab in combination with a taxane in the first line setting, followed by ado-trastuzumab emtansine on progression. Optimal treatment regimens in the third and greater line of therapy are not defined, but continued anti-HER2 therapy is recommended. Margetuximab is a Fc-modified monoclonal antibody to HER2 that recognizes the same epitope on HER2 as does trastuzumab, with similar affinity. Margetuximab demonstrates increased affinity to the activating CD16A Fc-receptor found on NK cells and macrophages and decreased affinity to the inhibitory CD32B receptor compared to trastuzumab. In vitro studies showed enhanced antibody dependent cell-mediated cytotoxicity compared to trastuzumab. In a Phase 1 dose escalation and expansion trial, margetuximab showed single agent clinical activity against HER2+ tumors in patients previously treated with trastuzumab and other anti-HER2 agents. Methods: SOPHIA is a randomized, prospective study testing the hypothesis that margetuximab plus chemotherapy (CTX) is more effective than trastuzumab plus CTX in patients previously treated for HER2+ MBC. Sequential primary endpoints are centrally assessed progression free survival (PFS) and overall survival (OS). The study size of 530 patients is determined to have 80% power to detect a hazard ratio for OS of 0.75. Secondary endpoints are investigator assessed PFS and centrally assessed overall response rate. Eligibility includes prior treatment with trastuzumab, pertuzumab, and ado-trastuzumab emtansine; no more than 3 prior lines of therapy in the metastatic setting; prior demonstration of HER2+ status at a local reference laboratory; and absence of active brain metastases. Eligible patients are randomized 1:1 to receive CTX (physician's choice: capecitabine, eribulin, gemcitabine or vinorelbine) plus either margetuximab or trastuzumab until disease progression or toxicity. Antibody may be continued after stopping CTX in patients with responding or stable disease. Progress to date: The trial was initiated July 2015 and is ongoing in the US and Europe with planned expansion to Korea and Israel. ClinicalTrials.gov Identifier NCT02492711; Eudract 2015-000380-13.
Citation Format: Rugo HS, Pegram MD, Gradishar WJ, Cortes J, Curigliano G, Hong S, Wigginton JM, Lechleider RJ, Cardoso F. SOPHIA: A phase 3, randomized study of margetuximab plus chemotherapy vs trastuzumab plus chemotherapy in the treatment of patients with HER2+ metastatic breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT1-02-07.</jats:p
Are Biosimilars the Future of Oncology and Haematology?
No full textBiological drugs are vital but often high-cost components of cancer treatment. Several biosimilar versions of these drugs have been approved in Europe and/or the USA, with many more in development. However, there is some disconnect between the biosimilars that are approved for use and those accessible in clinical practice, with availability impacted by factors including patent litigation and complex healthcare insurance policies, particularly in the USA. Provided the barriers to widespread uptake can be overcome, biosimilars offer potential benefits including cost savings and improved patient access versus the reference product (RP). This article provides an up-to-date and focused perspective on the development and use of biosimilars in the haemato-oncology setting. European and US regulatory pathways governing biosimilar licensing demand that there are no clinically meaningful differences between a biosimilar and its RP. Pathways are rigorously enforced and involve comprehensive non-clinical evaluations and clinical trials in selected indications to establish the equivalence or non-inferiority of efficacy, and the comparability of safety, of the biosimilar versus its RP. ‘Indication extrapolation’ is only permitted if scientifically justifiable considering mechanism(s) of action, pharmacokinetics, immunogenicity and safety in relevant patient populations. Switching treatment from RP to biosimilar is supported by most available data, predominantly from indications other than cancer, and post-marketing pharmacovigilance programmes are warranted. Notably, the potential benefits of biosimilar cancer treatment may extend beyond direct cost savings: for example, the availability of biosimilars of common regimen components may help incentivise the evaluation and/or clinical use of new treatment approaches and novel drugs
Early Evaluation of Risk Stratification and Clinical Outcomes for Patients with Advanced Breast Cancer through Combined Monitoring of Baseline Circulating Tumor Cells and DNA
No full textPurpose: Early evaluation of tumor heterogeneity related to metastasis and outcomes is a major challenge in the management of advanced breast cancer (BCa) in the clinic. In this study, we introduced the value of baseline circulating tumor cells (CTC) and ctDNA for early differentiation of clinical stages, tumor heterogeneity, and prognosis in clinic. Experimental Design: A total of 292 patients with BCa were enrolled in this study, including 254 Stage IV and 38 Stage III patients, and examined the baseline levels of CTCs, CTC-clusters, and plasma ctDNA before initiating therapies. Outcomes including progression-free survival (PFS) and overall survival were evaluated using proportional hazards regression analysis. Results: The baseline CTCs, including HER2+ CTCs, in Stage IV patients were approximately 9.5 times higher than those detected in Stage III patients. Baseline CTC counts with a cutoff of 5 were significantly associated with the prognosis. Within each stage, patients with <5 CTCs had significantly longer PFS. Stage III patients with no CTCs exhibited the longest survival compared with patients with ≥1 CTC. CTC-clusters were only found in Stage IV patients, among whom 15 Stage IV patients with ≥5 CTC-clusters had the worst PFS compared with the 239 Stage IV patients with <5 CTC-clusters. Similar outcomes were observed in 28 out of 254 Stage IV patients who had at least one CTC-cluster detected, as these patients had shorter PFS compared with CTC-cluster negative group. The major differences in ctDNA mutations between patients with Stage III and Stage IV BCa were in PIK3CA and ESR1, which were associated with specific organ metastasis and worse outcomes. Conclusions: Assessing the baseline levels of CTCs, CTC-clusters, and mutational ctDNA profile could reliably aid in differentiation of clinical stage and early prediction of metastasis and outcomes in advanced BCa
Performance of a novel Next Generation Sequencing circulating tumor DNA (ctDNA) platform for the evaluation of samples from patients with metastatic breast cancer (MBC)
No full textAlbumin-bound paclitaxel (ab-pac) versus docetaxel for first-line treatment of metastatic breast cancer (MBC): Final overall survival (OS) analysis of a randomized phase II trial.
No full text 275 Background: We previously reported the results of a phase II study evaluating the efficacy and safety of three different dosing regimens of ab-pac and docetaxel for the first-line treatment of MBC (Gradishar et al. J Clin Oncol. 2009;27:3611-3619). Here we report final OS outcomes. Methods: Patients (N = 300) with previously untreated MBC were randomized to 1 of 4 treatment arms (arms A–D listed in table). A step-down statistical approach was used for pairwise comparisons of treatment groups. Results: Patients (N = 300) with previously untreated MBC were randomized to 1 of 4 treatment arms (arms A–D listed in table). A step-down statistical approach was used for pairwise comparisons of treatment groups. These OS data were consistent with the investigator assessment of overall response rates (ORR) and progression-free survival (PFS) that were previously published. Rates of grade (gr) 3 sensory neuropathy (SN) were 21%, 9%, 22% and 12%, respectively in arms A, B,C, and D (p= 0.082). There were no cases of gr 4 SN. The median times to improvement to ≤ gr 2 SN were 22, 22, and 20 days for arms A, B, and C and 37 days for arm D. Gr 3/4 neutropenia occurred less frequently with ab-pac vs docetaxel (gr 3: 39, 20, 35, and 19% in arms A,B,C, and D, respectively; gr 4: 5, 5, 9, and 75%, p < .001 for gr 4). Conclusions: Ab-pac qw 3/4 at 150 mg/m2 resulted in a 33.8 mo OS, a longer OS than historically achieved with taxane monotherapy in MBC. The 150 mg/m2 qw 3/4 dosing regimen provided the best clinical outcome in this phase II trial in patients with MBC. [Table: see text] </jats:p
Association of a novel circulating tumor DNA next-generating sequencing platform with circulating tumor cells (CTCs) and CTC clusters in metastatic breast cancer
No full textLandscape of circulating tumour DNA in metastatic breast cancer
No full textBackground: We describe the genomic landscape of circulating tumour DNA (ctDNA) across pathological subtypes of metastatic breast cancer. Methods: 255 clinically annotated patients with ctDNA testing by Guardant360 were stratified into HR+, HER2+, and TNBC cohorts. Frequency and heterogeneity of alterations were reported. Paired ctDNA and tissue sequencing were compared for a subset of patients. The association of ctDNA and metastatic sites of disease on imaging was also assessed. Findings: 89% of patients had at least one ctDNA alteration detected. The most common single nucleotide variants (SNVs) for HR+ patients were PIK3CA, ESR1, and TP53. For HER2+, these were TP53, PIK3CA, and ERBB2 with ERBB2 as the most frequent copy number variant (CNV). For TNBC, the most common SNVs were TP53 and PIK3CA, and the most frequent CNVs were MYC, CCNE1, and PIK3CA. TNBC patients had a significantly higher mutant allele frequency (MAF) of the highest variant compared to HR+ or HER2+ patients (P<0.05). Overall, alterations in PIK3CA, ESR1, and ERBB2 were observed in 39.6%, 16.5%, and 21.6% of patients, respectively. Agreement between blood and tissue was 79–91%. MAF and number of alterations were significantly associated with number of metastatic sites on imaging (P<0.0001). Interpretation: These data demonstrate the genetic heterogeneity of metastatic breast cancer in blood, the high prevalence of clinically actionable alterations, and the potential to utilise ctDNA as a surrogate for tumour burden on imaging. Funding: Lynn Sage Cancer Research Foundation, OncoSET Precision Medicine Program, and REDCap support was funded by the National Institutes of Health UL1TR001422
Understanding the organ tropism of metastatic breast cancer through the combination of liquid biopsy tools
No full textBackground: Liquid biopsy provides real-time data about prognosis and actionable mutations in metastatic breast cancer (MBC). The aim of this study was to explore the combination of circulating tumour DNA (ctDNA) analysis and circulating tumour cells (CTCs) enumeration in estimating target organs more susceptible to MBC involvement. Methods: This retrospective study analysed 88 MBC patients characterised for both CTCs and ctDNA at baseline. CTCs were isolated through the CellSearch kit, while ctDNA was analysed using the Guardant360 NGS-based assay. Sites of disease were collected on the basis of imaging. Associations were explored both through uni- and multivariate logistic regression and Fisher's exact test and the random forest machine learning algorithm. Results: After multivariate logistic regression, ESR1 mutation was the only significant factor associated with liver metastases (OR 8.10), while PIK3CA was associated with lung localisations (OR 3.74). CTC enumeration was independently associated with bone metastases (OR 10.41) and TP53 was associated with lymph node localisations (OR 2.98). The metastatic behaviour was further investigated through a random forest machine learning algorithm. Bone involvement was described by CTC enumeration and alterations in ESR1, GATA3, KIT, CDK4 and ERBB2, while subtype, CTC enumeration, inflammatory BC diagnosis, ESR1 and KIT aberrations described liver metastases. PIK3CA, MET, AR, CTC enumeration and TP53 were associated with lung organotropism. The model, moreover, showed that AR, CCNE1, ESR1, MYC and CTC enumeration were the main drivers in HR positive MBC metastatic pattern. Conclusions: These results indicate that ctDNA and CTCs enumeration could provide useful insights regarding MBC organotropism, suggesting a possible role for future monitoring strategies that dynamically focus on high-risk organs defined by tumourbiology
The use of serial circulating tumor DNA to detect resistance alterations in progressive metastatic breast cancer
No full textPurpose: Circulating tumor DNA (ctDNA) is a promising tool for noninvasive longitudinal monitoring of genomic alterations. We analyzed serial ctDNA to characterize genomic evolution in progressive metastatic breast cancer. Experimental Design: This was a retrospective cohort between 2015 and 2019 obtained under an Institutional Review Board-approved protocol at Northwestern University (Chicago, IL). ctDNA samples were analyzed with Guardant360 next-generation sequencing (NGS) assay. A total of 86 patients had at least two serial ctDNA collections with the second drawn at first post-NGS progression (PN1) by imaging and clinical assessment. A total of 27 participants had ctDNA drawn at second post-NGS clinical progression (PN2). We analyzed alterations, mutant allele frequency (MAF), number of alterations (NOA), and sites of disease on imaging in close proximity to ctDNA evaluation. Matched pairs' variations in MAF, NOA, and alterations at progression were tested through Wilcoxon test. We identified an independent control cohort at Massachusetts General Hospital (Boston, MA) of 63 patients with serial ctDNA sampling and no evidence of progression. Results: We identified 44 hormone receptor-positive, 20 HER2þ, and 22 triple-negative breast cancer cases. The significant alterations observed between baseline and PN1 were TP53 (P < 0.0075), PIK3CA (P < 0.0126), AR (P < 0.0126), FGFR1 (P < 0.0455), and ESR1 (P < 0.0143). Paired analyses revealed increased MAF and NOA from baseline to PN1 (P 1⁄4 0.0026, and P < 0.0001, respectively). When compared with controls without progression, patients with ctDNA collection at times of progression were associated with increased MAF and NOA (P 1⁄4 0.0042 and P < 0.0001, respectively). Conclusions: Serial ctDNA testing identified resistance alterations and increased NOA and MAF were associated with disease progression. Prospective longitudinal ctDNA evaluation could potentially monitor tumor genomic evolution
Longitudinal dynamics of circulating tumor cells and circulating tumor DNA for treatment monitoring in metastatic breast cancer
No full textPURPOSE: Liquid biopsy-based biomarkers, including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA), are increasingly important for the characterization of metastatic breast cancer (MBC). The aim of the study was to explore CTCs and ctDNA dynamics to better understand their potentially complementary role in describing MBC. METHODS: The study retrospectively analyzed 107 patients with MBC characterized with paired CTCs and ctDNA assessments and a second prospective cohort, which enrolled 48 patients with MBC. CTCs were immunomagnetically isolated and ctDNA was quantified and then characterized through next-generation sequencing in the retrospective cohort and droplet digital polymerase chain reaction in the prospective cohort. Matched pairs variations at baseline, at evaluation one (EV1), and at progression were tested through the Wilcoxon test. The prognostic role of ctDNA parameters was also investigated. RESULTS: Mutant allele frequency (MAF) had a significant decrease between baseline and EV1 and a significant increase between EV1 and progression. Number of detected alterations steadily increased across timepoints, CTCs enumeration (nCTCs) significantly increased only between EV1 and progression. MAF dynamics across the main altered genes was then investigated. Plasma DNA yield did not vary across timepoints both in the retrospective cohort and in the prospective cohort, while the short fragments fraction showed a potential role as a prognostic biomarker. CONCLUSION: nCTCs and ctDNA provide complementary information about prognosis and treatment benefit. Although nCTCs appeared to assess tumor biology rather than tumor burden, MAF may be a promising biomarker for the dynamic assessment of treatment response and resistance
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