ORCID Profile
0000-0003-0411-0736
Current Organisations
Australian National University
,
Monash Health
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Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478804
Abstract: Baseline characteristics of studied c-TREnd biomarker population - including all patients with at least one s le available for analysis at any timepoint(s), compared to the overall original TREnd cohort. Fisher exact test was used to calculate p-values. *Denotes patients included in intention-to-treat population of TREnd, despite breach of eligibility criteria (discovered post-enrolment).
Publisher: Elsevier BV
Date: 05-2020
Publisher: Anticancer Research USA Inc.
Date: 30-07-2018
DOI: 10.21873/ANTICANRES.12795
Abstract: The combination of platinum with 5-fluorouracil has scarcely been studied in metastatic breast cancer. As this combination does not lead to significant hepatic metabolism, in some clinical situations it may prove useful, especially in cases with liver dysfunction and an urgent clinical need for rapid tumor shrinkage. A retrospective study was conducted to evaluate the efficacy and safety of the combination of cisplatin and 5-fluorouracil in patients with metastatic breast cancer with significant alterations of biochemistry. A total of 109 patients with metastatic breast cancer and liver dysfunction were treated time-to-progression, overall survival and trends in liver function were evaluated. The median time-to-progression was 3.4 months, and median overall survival was 7.8 months. About 50% of patients obtained a complete, partial or stable biochemical response and 24 patients were subsequently able to receive additional therapies. Our results show that this therapeutic doublet represents a clinically effective, safe and well-tolerated treatment option for patients with metastatic breast cancer and liver dysfunction.
Publisher: Impact Journals, LLC
Date: 25-09-2018
Publisher: MDPI AG
Date: 30-11-2020
Abstract: In the treatment of advanced non-small cell lung cancer (NSCLC), immune checkpoint inhibitors have shown remarkable results. However, not all patients with NSCLC respond to this drug treatment or receive durable benefits. Thus, patient stratification and selection, as well as the identification of predictive biomarkers, represent pivotal aspects to address. In this framework, metabolomics can be used to support the discrimination between responders and non-responders. Here, metabolomics was used to analyze the sera s les from 50 patients with NSCL treated with immune checkpoint inhibitors. All the s les were collected before the beginning of the treatment and were analyzed by NMR spectroscopy and multivariate statistical analyses. Significantly, we show that the metabolomic fingerprint of serum acts as a predictive “collective” biomarker to immune checkpoint inhibitors response, being able to predict in idual therapy outcome with 80% accuracy. Metabolomics represents a potential strategy for the real-time selection and monitoring of patients treated with immunotherapy. The prospective identification of responders and non-responders could improve NSCLC treatment and patient stratification, thus avoiding ineffective therapeutic strategies.
Publisher: Wiley
Date: 18-01-2022
DOI: 10.1111/AJCO.13754
Abstract: People with cancer are at higher risk of serious illness and death from COVID‐19 infection. We investigated COVID‐19 vaccine uptake among patients with solid organ and blood cancers and explored factors related to hesitancy. Cross‐sectional online survey of adults with a history of cancer at three health services across metropolitan and regional Victoria. Vaccine hesitancy was measured by the validated Oxford COVID‐19 vaccine hesitancy scale. There were 1073 respondents: 56% female median age 62 years (range 23 ‐ 91). Commonest tumor types included breast 29%, gastrointestinal 19%, hematological 15%, genitourinary 15%, and lung 8%. Thirty‐six percent had metastatic disease, and 54% were receiving active anticancer treatment. Eighty‐four percent of respondents indicated positive intent toward COVID‐19 vaccination, 10% were undecided, and 6% indicated negative attitudes. At least one vaccine dose had been received by 65% of respondents, leaving 35% unvaccinated. Fifty‐eight percent of unvaccinated patients answered that they would “definitely” or “probably” take a vaccine. Higher vaccine uptake was significantly associated with older age, male gender, English as first language, longer time since cancer diagnosis, and not being on current anticancer treatment. Concerns regarding vaccine side effects, particularly thrombosis, and the desire for clear medical advice were prominent among unvaccinated respondents. Despite being eligible for COVID‐19 vaccination since March 2021, a substantial minority of patients with cancer remained unvaccinated as of August 2021. Targeted communication and educational resources addressing vaccine safety in the context of cancer are key to promoting vaccine uptake in this vulnerable population.
Publisher: Springer Science and Business Media LLC
Date: 24-03-2021
DOI: 10.1186/S13058-021-01415-W
Abstract: Circulating tumor cells (CTCs) are prognostic in patients with advanced breast cancer (ABC). However, no data exist about their use in patients treated with palbociclib. We analyzed the prognostic role of CTC counts in patients enrolled in the cTREnd study, a pre-planned translational sub-study of TREnd (NCT02549430), that randomized patients with ABC to palbociclib alone or palbociclib plus the endocrine therapy received in the prior line of treatment. Moreover, we evaluated RB1 gene expression on CTCs and explored its prognostic role within the cTREnd subpopulation. Forty-six patients with ER-positive, HER2-negative ABC were analyzed. Blood s les were collected before starting palbociclib treatment (timepoint T0), after the first cycle of treatment (timepoint T1), and at disease progression (timepoint T2). CTCs were isolated and counted by CellSearch® System using the CellSearch™Epithelial Cell kit. Progression-free survival (PFS), clinical benefit (CB) during study treatment, and time to treatment failure (TTF) after study treatment were correlated with CTC counts. S les with ≥ 5 CTCs were sorted by DEPArray system® (DA). RB1 and GAPDH gene expression levels were measured by ddPCR. All 46 patients were suitable for CTCs analysis. CTC count at T0 did not show significant prognostic value in terms of PFS and CB. Patients with at least one detectable CTC at T1 ( n = 26) had a worse PFS than those with 0 CTCs ( n = 16) ( p = 0.02). At T1, patients with an increase of at least three CTCs showed reduced PFS compared to those with no increase (mPFS = 3 versus 9 months, ( p = 0.004). Finally, patients with ≥ 5 CTCs at T2 ( n = 6/23) who received chemotherapy as post-study treatment had a shorter TTF ( p = 0.02). Gene expression data for RB1 were obtained from 19 patients. CTCs showed heterogeneous RB1 expression. Patients with detectable expression of RB1 at any timepoint showed better, but not statistically significant, outcomes than those with undetectable levels. CTC count seems to be a promising modality in monitoring palbociclib response. Moreover, CTC count at the time of progression could predict clinical outcome post-palbociclib. RB1 expression analysis on CTCs is feasible and may provide additional prognostic information. Results should be interpreted with caution given the small studied s le size.
Publisher: American Medical Association (AMA)
Date: 02-2020
Publisher: Elsevier BV
Date: 08-2021
DOI: 10.1016/J.CLBC.2020.11.010
Abstract: Metronomic chemotherapy can induce disease control in patients with metastatic breast cancer (MBC) and has better safety profiles than conventional chemotherapy. Evidence suggests that cytotoxics can be anti-angiogenic in pre-clinical models and may have synergistic effects when combined with anti-vascular endothelial growth factor therapies. Patients pretreated with ≥ 1 prior line of therapy for MBC received oral cyclophosphamide 50 mg daily in combination with oral vinorelbine at escalating doses of 20 mg (V20), 30 mg (V30), and 40 mg (V40) 3 times per week, and intravenous bevacizumab 15 mg/kg every 3 weeks. Patients with human epidermal growth factor receptor 2-positive disease were given the same regimen plus standard trastuzumab. Doses were escalated when 3 patients completed 3 treatment cycles of V20 and V30, without experiencing dose-limiting toxicities. The recommended dose was then tested in a further 6 patients. Circulating tumour cells and circulating endothelial cells (CEC) were measured in 30 mL of whole blood s les at baseline, after cycle 1, and at the disease progression. Fifteen patients were recruited from June 2013 to October 2015. The median age was 61 years (range, 29-72 years) 80% had estrogen receptor-positive and 33% had human epidermal growth factor receptor 2-positive disease. At least 67% had visceral metastases, and 80% had received ≥ 2 lines of prior treatment. No dose-limiting toxicities were observed at the 3 dose-levels, making V40 the recommended dose. Overall 8 (53%) patients developed grade 2 adverse events (arthralgia, n = 3 [20%] asthenia, n = 2 [13%] diarrhea, n = 2 [13%] leukopenia, n = 2 [13%]). Bevacizumab was associated with grade 3 hypertension (n = 3 [20%]). Stable disease as best response was observed in 11 (73.3%) patients. The clinical benefit rate was 66.6% (10/15 patients). The median time to progression was 6.9 months. At baseline, CECs were more commonly detectable than circulating tumor cells however, no statistical correlation was found between CEC kinetics and response. A metronomic vinorelbine dose of 40 mg combined with cyclophosphamide and bevacizumab is a promising treatment regimen in pretreated patients with MBC.
Publisher: American Medical Association (AMA)
Date: 10-2020
Publisher: Elsevier BV
Date: 11-2019
Publisher: Elsevier BV
Date: 09-2022
Publisher: Springer Science and Business Media LLC
Date: 29-08-2019
DOI: 10.1038/S41523-019-0123-9
Abstract: Despite recent refinements to the 21-gene g score, allowing a better identification of patients who may derive no benefit from the addition of adjuvant chemotherapy to that of endocrine therapy, patients with early breast cancer still stand to be over-treated in the setting of clinical and/or genomic uncertainty or discordance. Here we describe and demonstrate a potential approach of further refining the OncotypeDX risk score by metabolomic analysis of serum. In a clinical dataset ( N = 87), the risk of recurrence was further sub-stratified by metabolomic signature, with an effective splitting of each Oncotype risk classification. A total of seven recurrences were recorded, with metabolomic analysis accurately predicting six of these. Contrastingly, the genomic risk score of the seven recurrences ranged across all three Oncotype classifications (one recurrence occurred in the “low”-risk group, three in the “intermediate” group and three in the “high”-risk group).
Publisher: MDPI AG
Date: 02-06-2021
Abstract: Adjuvant treatment for patients with early stage colorectal cancer (eCRC) is currently based on suboptimal risk stratification, especially for elderly patients. Metabolomics may improve the identification of patients with residual micrometastases after surgery. In this retrospective study, we hypothesized that metabolomic fingerprinting could improve risk stratification in patients with eCRC. Serum s les obtained after surgery from 94 elderly patients with eCRC (65 relapse free and 29 relapsed, after 5-years median follow up), and from 75 elderly patients with metastatic colorectal cancer (mCRC) obtained before a new line of chemotherapy, were retrospectively analyzed via proton nuclear magnetic resonance spectroscopy. The prognostic role of metabolomics in patients with eCRC was assessed using Kaplan–Meier curves. PCA-CA-kNN could discriminate the metabolomic fingerprint of patients with relapse-free eCRC and mCRC (70.0% accuracy using NOESY spectra). This model was used to classify the s les of patients with relapsed eCRC: 69% of eCRC patients with relapse were predicted as metastatic. The metabolomic classification was strongly associated with prognosis (p-value 0.0005, HR 3.64), independently of tumor stage. In conclusion, metabolomics could be an innovative tool to refine risk stratification in elderly patients with eCRC. Based on these results, a prospective trial aimed at improving risk stratification by metabolomic fingerprinting (LIBIMET) is ongoing.
Publisher: Apollo - University of Cambridge Repository
Date: 2022
DOI: 10.17863/CAM.85002
Publisher: MDPI AG
Date: 28-11-2019
Abstract: Mutations in the hotspot ligand-binding domain of the estrogen receptor (ER) gene ESR1 have recently been recognized as mechanisms of endocrine resistance in endocrine receptor-positive metastatic breast cancer (MBC). Accumulating data suggest these mutations develop under the selective pressure of endocrine treatments, and are infrequent in untreated ER-positive breast cancers. In vitro studies show that these mutations confer ligand-independent activity, resistance to estrogen deprivation, and relative resistance to tamoxifen and fulvestrant. Post-hoc retrospective and prospective analyses of ESR1 mutations in patients with MBC have consistently found that these mutations are markers of poor prognosis and predict resistance to aromatase inhibitors (AIs). These results warrant further investigation and prospective validation in dedicated studies. Moreover, studies are ongoing to clarify the activity of novel drugs in the context of metastatic endocrine resistant luminal breast cancer harboring ESR1 mutations. In this review, we summarize the pre-clinical and clinical findings defining the characteristics of ESR1 mutant breast cancer, and highlight the potential clinical developments in this field.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530048.V1
Abstract: AbstractPurpose: Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both i in vitro /i and in patients with ABC. Experimental Design: Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor–positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the “To Reverse ENDocrine Resistance” (TREnd) trial ( i n /i = 46). Results: Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients ( i n /i = 8) showing an increase—correlating with a worse outcome than those with decreased/stable TKa ( i n /i = 33 mPFS 3.0 vs 9.0 months i P /i = 0.002). At T2, mTKa was 251 Du/L patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months i P /i = 0.05). Conclusions: TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib. /
Publisher: Elsevier BV
Date: 05-2022
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2022
DOI: 10.1158/1538-7445.SABCS21-OT1-02-02
Abstract: Background: The HER2 receptor is a cancer driver which is overexpressed on 15-20% of breast cancers. Though historically survival is poor with this disease subtype, HER2+ targeted therapy has improved survival in both early and advanced disease. In spite of this, most patients in the metastatic setting will eventually experience disease progression and death. Therefore, new therapeutic options and innovative treatments are needed for patients with recurrent or refractory disease. ARX788 is a next-generation antibody–drug conjugates (ADC) using a technology platform whereby a HER2 specific monoclonal antibody is conjugated with Amberstatin269, a potent cytotoxic tubulin inhibitor. Site-specific, high homogenous, and stable covalent conjugation in ARX788 leads to slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity, increased targeted delivery of payload to tumor cells, and lower effective dose compared to other HER2 ADCs.Methods: ACE-Breast-03 (NCT04829604) is a global, single arm, phase 2 study designed to assess anticancer activity and safety of ARX788 in patients with metastatic HER2 positive breast cancer. Patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens are eligible. Patients must have adequate organ function and any brain metastasis must demonstrate radiographic stability and lack of steroid dependence. Approximately 200 subjects with advanced HER2-positive breast cancer will be enrolled. ARX788 will be administered as an intravenous (IV) infusion at 1.5 mg/kg as the initial dose on Day 1 of the first 4-week cycle and followed by 1.3 mg/kg at every subsequent 4-week cycle. Efficacy will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1 via imaging every 8 weeks (±7 days) on study and endpoints include objective response rate (ORR), duration of response (DOR), time to response (TTR), best overall response (BOR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). The safety and tolerability profile will be assessed. Blood s les will be collected at specified time points to determine serum concentrations of ARX788 (intact ADC), total antibody, and metabolite pAF-AS269. Biomarkers (e.g., cell-free DNA, serum HER2 extracellular domain, and circulating tumor cells) at baseline and on-treatment will be analyzed for exploratory research. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Please contact breast03trialinquiry@ambrx.com for additional information. Citation Format: Janice Lu, Kevin M Kalinsky, Debu Tripathy, George W Sledge, William Gradishar, Ruth O’Regan, Joyce O’Shaughnessy, Shanu Modi, Joshua Drago, Haeseong Park, Amelia McCartney, Sophia Frentzas, Catherine Shannon, Katharine Cuff, Richard Eek, Miguel Idzwan Martin, Giuseppe Curigliano, Guy Jerusalem, Chiun-Sheng Huang, Michael Press, Matt Li, Dong Xu, Cynthia Song, Richard Huhn, Jinchun Yan, Sara Hurvitz. A global, phase 2 study of ARX788 in patients with HER2-positive metastatic breast cancer whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium 2021 Dec 7-10 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2022 (4 Suppl):Abstract nr OT1-02-02.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 12-2019
DOI: 10.1200/JGO.19.00251
Publisher: MDPI AG
Date: 26-05-2022
Abstract: As COVID-19 vaccinations became available and were proven effective in preventing serious infection, uptake amongst in iduals varied, including in medically vulnerable populations. This cross-sectional multi-site study examined vaccine uptake, hesitancy, and explanatory factors amongst people with serious and/or chronic health conditions, including the impact of underlying disease on attitudes to vaccination. A 42-item survey was distributed to people with cancer, diabetes, or multiple sclerosis across ten Australian health services from 30 June to 5 October 2021. The survey evaluated sociodemographic and disease-related characteristics and incorporated three validated scales measuring vaccine hesitancy and vaccine-related beliefs generally and specific to their disease: the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale-Six. Among 4683 participants (2548 [54.4%] female, 2108 [45.0%] male, 27 [0.6%] other mean [SD] age, 60.6 [13.3] years 3560 [76.0%] cancer, 842 [18.0%] diabetes, and 281 [6.0%] multiple sclerosis), 3813 (81.5%) self-reported having at least one COVID-19 vaccine. Unvaccinated status was associated with younger age, female sex, lower education and income, English as a second language, and residence in regional areas. Unvaccinated participants were more likely to report greater vaccine hesitancy and more negative perceptions toward vaccines. Disease-related vaccine concerns were associated with unvaccinated status and hesitancy, including greater complacency about COVID-19 infection, and concerns relating to vaccine efficacy and impact on their disease and/or treatment. This highlights the need to develop targeted strategies and education about COVID-19 vaccination to support medically vulnerable populations and health professionals.
Publisher: Springer Science and Business Media LLC
Date: 22-03-2018
DOI: 10.1007/S10549-018-4766-2
Abstract: HER2-positive (HER2+) breast cancers show heterogeneous response to chemotherapy, with the ER-positive (ER+) subgroup deriving less benefit. Loss of retinoblastoma tumor suppressor gene (RB1) function has been suggested as a cardinal feature of breast cancers that are more sensitive to chemotherapy and conversely resistant to CDK4/6 inhibitors. We performed a retrospective analysis exploring RBsig, a gene signature of RB loss, as a potential predictive marker of response to neoadjuvant chemotherapy in ER+/HER2+ breast cancer patients. We selected clinical trials of neoadjuvant chemotherapy ± anti-HER2 therapy in HER2+ breast cancer patients with available information on gene expression data, hormone receptor status, and pathological complete response (pCR) rates. RBsig expression was computed in silico and correlated with pCR. Ten studies fulfilled the inclusion criteria and were included in the analysis (514 patients). Overall, of 211 ER+/HER2+ breast cancer patients, 49 achieved pCR (23%). The pCR rate following chemotherapy ± anti-HER2 drugs in patients with RBsig low expression was significantly lower compared to patients with RBsig high expression (16% vs. 30%, respectively Fisher's exact test p = 0.015). The area under the ROC curve (AUC) was 0.62 (p = 0.005). In the 303 ER-negative (ER-)/HER2+ patients treated with chemotherapy ± anti-HER2 drugs, the pCR rate was 43%. No correlation was found between RBsig expression and pCR rate in this group. Low expression of RBsig identifies a subset of ER+/HER2+ patients with low pCR rates following neoadjuvant chemotherapy ± anti-HER2 therapy. These patients may potentially be spared chemotherapy in favor of anti-HER2, endocrine therapy, and CDK 4/6 inhibitor combinations.
Publisher: SAGE Publications
Date: 2018
Abstract: Until recently, the mainstay of treatment in the majority of hormone receptor (HR)-positive, human epidermal growth factor 2 receptor (HER2)-negative advanced breast cancer (ABC) has consisted of single-agent endocrine therapy (ET). However, as understanding of endocrine resistance has grown, newer targeted agents have come to the fore. Inhibition of cyclin-dependent kinase complexes 4 and 6 (CDK4/6) combined with ET has shown significant activity in HR+ HER2− ABC, with impressive results in terms of progression-free survival (PFS) when compared with ET alone. This review summarizes the seminal findings pertaining to CDK4/6 inhibition in this population, specifically focusing on abemaciclib, contrasted with palbociclib and ribociclib. Potential directions for future studies are discussed, as a way of addressing outstanding issues such as establishing optimal treatment sequencing and agent combinations, appropriate patient selection to derive maximal benefits, predictive biomarkers and the employment of CDK4/6 inhibition beyond the ABC setting.
Publisher: Elsevier BV
Date: 10-2019
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.EJCA.2019.04.002
Abstract: Thymidine kinase 1 (TK1) plays a critical role in DNA synthesis and cell proliferation. Recent studies have shown potential for serum TK1 activity (sTKa) as a prognostic marker and indicator of early response to endocrine therapy in advanced breast cancer. The aim of this study is to assess the correlation between sTKa and patient outcome. The Evaluation of Faslodex versus Exemestane Clinical Trial (EFECT) was a double-blind, double-dummy, randomised trial of fulvestrant versus exemestane after progression on non-steroidal aromatase inhibitor therapy, in postmenopausal women with advanced breast cancer. Retrospective analyses of serum archived from EFECT were conducted. sTKa was assessed using the DiviTum® assay on s les collected at baseline, after three and six months of endocrine therapy, and at disease progression. The median time to progression (mTTP) for patients with low baseline sTKa levels was 5.03 months (95% confidence interval [CI]: 3.91-5.89) versus 2.57 months (95% CI: 2.04-3.52) in patients with high sTKa baseline levels (P < 0.0001). On treatment, patients whose sTKa increased from baseline had a significantly shorter mTTP (3.39 months, 95% CI: 2.14-4.11) than those without an sTKa increase (5.39 months, 95% CI: 4.01-6.68) (P = 0.0045). Similar results were observed in the separate EFECT treatment arms. After adjusting for major prognostic factors, sTKa remained an independent marker. sTKa is a potential circulating prognostic marker in patients with advanced breast cancer treated with endocrine therapy. It may also represent a tool for upfront identification of endocrine therapy resistance and early positive response to therapy. Independent validation of these results is warranted.
Publisher: Frontiers Media SA
Date: 23-07-2019
Publisher: Elsevier BV
Date: 09-2022
Publisher: American Association for Cancer Research (AACR)
Date: 03-2023
DOI: 10.1158/1538-7445.SABCS22-P5-02-27
Abstract: Background: Thymidine kinase-1 is a cell proliferation marker downstream of the CDK4/6 pathway, whose activity can be measured in serum to reflect tumor proliferation. The CDK4/6 inhibitor palbociclib (P) is approved for the treatment of patients (pts) with hormone receptor positive metastatic breast cancer (MBC) in first or second line endocrine-based treatment settings. Approximately 10-15% of pts exhibit de novo resistance to P, with circulating levels of thymidine kinase activity (TKa) previously shown as a potential marker of early treatment resistance. Therapeutic strategies to address primary resistance to P are currently lacking. Little is known of the clinical efficacy of alternative dosing schedules of P, and its effect on TKa. Here we report serum TKa measured at different timepoints from s les collected within the MA38 (NCT02630693) study. Methods: MA38 is an open label randomised Phase 2 trial comparing two different schedules of P plus second-line ET in pts with ER-positive, HER2-negative MBC. Pts were assigned to receive physician’s choice ET plus either standard P dosing (125mg daily for 21 days on a 28-day cycle), or 100mg daily continuously. Serum s les were collected at baseline (BL n=135), at 12 weeks (W12 n=122) and 24 weeks (W24 n=95). TKa was measured with DiviTum®, a refined ELISA-based assay (lower limit of detection [LLOD] = 100 DuA). Kaplan-Meier method estimated BL, W12 and W24 (95% CI) median PFS (mPFS from randomization until progression by RECIST criteria or death) and overall survival (OS from randomization until death from any cause) in groups of patients defined by dichotomizing TKa as “high” or “low” at the median. Results: MA38 enrolled 180 pts from December 2015 and February 2017 across Canada. Median follow up was 19 months. Overall, the median age was 60, and 90% of pts were post-menopausal. All pts had estrogen receptor-positive disease, and 64% had visceral metastases. On study, 56% received fulvestrant with P, 34% aromatase inhibitor and 10% tamoxifen. TKa was successfully measured in 100% of s les. Median TKa (mTKa) at BL was 234 DuA (IQR 138.5 - 438). BL TKa was not associated with clinical or pathological characteristics. TKa was prognostic at BL with mPFS of 5.5 months (mo) in pts with high TKa vs 16.3 mo with low TKa (HR=2.43 95% CI, 1.6-3.7 p& 0.001). Similar results were obtained employing other previously reported cut off values. At multivariate analysis, BL TKa was independent from other prognostic factors including age, ECOG status and presence of visceral metastases (adjusted HR= 2.34 95%CI 1.5- 3.6 p & 0.001). In terms of OS, BL TKa was an independent prognostic factor (adjusted HR=2.0 95% CI, 1.1-3.7 p=0.02). At 12 mo, OS rate was 68% in pts with high BL TKa vs 92% in low TKa. Both for PFS and OS, no interaction between BL TKa and study arm was observed. At W12 mTKa was 129.5 DuA (IQR 100 - 219.8) and below LLOD (IQR 100 - 180) at W24. At these timepoints, landmark analyses showed no significant difference in PFS according to TKa. However, at W12 high TKa was significantly associated with worse OS (HR 2.0 95%CI 1.0- 4.0 p=0.03), with a similar trend at W24 (HR 2.5 95%CI 0.9-6.4 p=0.06). Conclusions: Baseline TKa is a reliable prognostic marker of both PFS and OS in pts treated with P and ET, further substantiating previous data. Monitoring TKa during treatment may provide important clinical information. A significant relationship between TKa and assigned treatment arm was not observed, suggesting TKa is not influenced by P treatment dose or intensity. These data confirm the role of baseline TKa as a new marker for patient stratification, and supports further investigation for the assessment of the clinical utility of TKa as a monitoring biomarker in the advanced setting. Citation Format: Amelia McCartney, Chiara Biagioni, Bingshu Chen, Lois Shepherd, Karen Gelmon, Anil A. Joy, Wendy Parulekar, Mattias Bergqvist, Ilenia Migliaccio, Angela Leo, Matteo Benelli, Emanuela Risi, Erica Moretti, Luca Livraghi, Laura Biganzoli, Luca Malorni. Serum thymidine kinase activity as a prognostic marker in women with metastatic breast cancer treated with two different schedules of palbociclib plus second-line endocrine therapy within the CCTG MA38 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium 2022 Dec 6-10 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2023 (5 Suppl):Abstract nr P5-02-27.
Publisher: Elsevier BV
Date: 03-2019
Publisher: Springer International Publishing
Date: 2019
Publisher: Elsevier BV
Date: 02-2021
Publisher: SAGE Publications
Date: 2018
Abstract: The current therapeutic landscape of luminal human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (mBC) is fundamentally evolving, particularly in the advent of molecularly targeted therapies, such as inhibitors of mammalian target of rapamycin and cyclin-dependent kinase 4/6 (CDK4/6). In the context of CDK4/6 inhibitors, landmark clinical trials for palbociclib (PALOMA-1, PALOMA-2, PALOMA-3), ribociclib (MONALEESA-2, MONALEESA-3, MONALEESA-7) and abemaciclib (MONARCH-1, MONARCH-2, MONARCH-3) have provided solid data regarding progression-free survival and overall response rate, justifying the introduction of this class of drugs into our therapeutic armoury. However, several clinical questions remain open. One of the most relevant issues faced in practice is that of the optimum sequencing of CDK4/6 inhibitors, particularly given the wide range of therapeutic options open to clinicians treating luminal mBC. In this brief commentary, we would like to focus on the best sequence for CDK4/6 inhibitors and their place in this growing, complex scenario.
Publisher: Elsevier BV
Date: 11-2017
Publisher: Elsevier BV
Date: 07-2021
Publisher: Future Medicine Ltd
Date: 05-2020
Publisher: AME Publishing Company
Date: 06-2020
Publisher: Cold Spring Harbor Laboratory
Date: 06-04-2022
DOI: 10.1101/2022.04.06.22273080
Abstract: To examine vaccine uptake, hesitancy and explanatory factors amongst people with serious and/or chronic health conditions, including the impact of underlying disease on attitudes to vaccination. Cross-sectional survey. Ten Australian health services. 4683 patients (3560 cancer, 842 diabetes and 281 multiple sclerosis) receiving care at the health services participated in the 42-item survey, between June 30 to October 5, 2021. Sociodemographic and disease-related characteristics, COVID-19 vaccine uptake, and the scores of three validated scales which measured vaccine hesitancy and vaccine-related beliefs generally and specific to the participants’ disease, including the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale. Multivariable logistic regression was used to determine the associations between scale scores and vaccine uptake. Of all participants, 81.5% reported having at least one COVID-19 vaccine. Unvaccinated status was associated with younger age, female sex, lower education and income, English as a second language, and residence in regional areas (all p .05). Unvaccinated participants were more likely to report greater vaccine hesitancy and more negative perceptions toward vaccines (all p .05). Disease-related vaccine concerns were associated with unvaccinated status and hesitancy, including greater complacency about COVID-19 infection, and concerns relating to vaccine efficacy and impact on their disease and/or treatment (all p .05). Disease-specific concerns impact COVID-19 vaccine-related behaviours and beliefs in people with serious and/or chronic health conditions. This highlights the need to develop targeted strategies and education about COVID-19 vaccination to support medically vulnerable populations and health professionals. ACTRN12621001467820
Publisher: Springer Science and Business Media LLC
Date: 05-08-2020
DOI: 10.1186/S13058-020-01319-1
Abstract: Limited data are available regarding the use of nab-paclitaxel in older patients with breast cancer. A weekly schedule is recommended, but there is a paucity of evidence regarding the optimal dose. We evaluated the efficacy of two different doses of weekly nab-paclitaxel, with a specific focus on their corresponding impact on patient function, in order to address the lack of data specifically relating to the older population. EFFECT is an open-label, phase II trial wherein 160 women with advanced breast cancer aged ≥ 65 years were enrolled from 15 institutions within Italy. Patients were randomly assigned 1:1 to receive nab-paclitaxel 100 mg/m 2 (arm A) or 125 mg/m 2 (arm B) on days 1, 8, and 15 on a 28-day cycle, as first-line treatment for advanced disease. The primary endpoint was event-free survival (EFS), wherein an event was defined as disease progression (PD), functional decline (FD), or death. In each arm, the null hypothesis that the median EFS would be ≤ 7 months was tested against a one-sided alternative according to the Brookmeyer Crowley test. Secondary endpoints included objective response rate (ORR), clinical benefit rate (CBR), progression-free survival (PFS), overall survival (OS), and safety. After a median follow-up of 32.6 months, 140 events were observed in 158 evaluable patients. Median EFS was 8.2 months (90% CI, 5.9–8.9 p = 0.188) in arm A vs 8.3 months (90% CI, 6.2–9.7, p = 0.078) in arm B. Progression-free survival, overall survival, and response rates were similar in both groups. A higher percentage of dose reductions and discontinuations due to adverse events (AEs) was noted in arm B. The most frequently reported non-haematological AEs were fatigue (grade [G] 2–3 toxicity occurrence in arm A vs B, 43% and 51%, respectively) and peripheral neuropathy (G2–3 arm A vs B, 19% and 38%, respectively). Pre-specified outcomes were similar in both treatment arms. However, 100 mg/m 2 was significantly better tolerated with fewer neurotoxicity-related events, representing a more feasible dose to be recommended for older patients with advanced disease. EudraCT, 2012-002707-18 . Registered on June 4, 2012. NIH ClinicalTrials.gov, NCT02783222 . Retrospectively registered on May 26, 2016.
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2020
DOI: 10.1158/1538-7445.SABCS19-ES8-1
Abstract: Adjuvant endocrine therapy in 2020: It’s complicated Data regarding the use of adjuvant endocrine therapy in patients with hormone receptor-positive early breast cancer has grown over the past decades, and yet still uncertainty remains in management recommendations. In pre-menopausal women, treatment decisions are often driven by estimation of risk of recurrence, measured in terms of clinical and pathological parameters, algorithm-based prognostic modelling derived from breast cancer registries, molecular profiling and gene signature assays. Despite these significant advances, risk of distant disease recurrence is still over-estimated in a significant proportion of women. The addition of ovarian suppression to tamoxifen in pre-menopausal women has been shown to increase rates of both disease-free survival and overall survival than tamoxifen alone, with the use of the steroidal aromatase inhibitor exemestane producing further higher rates of freedom from recurrence. However, the addition of ovarian suppression in this generally low-risk population comes at the cost of increased adverse events and potential to interpose child-bearing years. Further to this, the SOFT/TEXT studies mandated five years of active treatment little is known as to whether extended treatment beyond those five years would be comparatively equal, better or worse in terms of outcome endpoints. In the post-menopausal population, the updated ASCO Clinical Practice Guideline suggests that all women with node-positive disease should be offered extended therapy including an aromatase inhibitor for a total of ten years, as well as women with node-negative disease possessing high-risk prognostic factors. The question of how best to identify those women who may fare equally well with de-escalated, shorter therapy remains open. The issue of adverse events and drug-related side effects, particularly in the setting of extended therapy, is relevant and may impact negatively on overall treatment compliance and quality of life. As such, the choice of endocrine therapy remains an important consideration, as is evidence that intermittent administration of aromatase inhibitors may be feasible in selected patients. CDK4/6 inhibitors, administered in tandem with endocrine therapy, have radically changed the approach to managing metastatic endocrine receptor-positive disease. There is now much interest in moving these agents forward into the neoadjuvant and adjuvant setting, with a number of phase II and III trials ongoing. If positive data is consistently reported in adjuvant studies, this will undoubtedly create another layer of complexity to the clinical management of endocrine-sensitive disease. Citation Format: A McCartney, A Di Leo. Adjuvant endocrine therapy in 2020: It's complicated [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium 2019 Dec 10-14 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2020 (4 Suppl):Abstract nr ES8-1.
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.CLBC.2019.05.019
Abstract: The landscape of therapeutic options for the treatment of hormone receptor (HR)-positive (HR
Publisher: Elsevier BV
Date: 09-2017
Publisher: Informa UK Limited
Date: 07-1999
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22478804.V1
Abstract: Baseline characteristics of studied c-TREnd biomarker population - including all patients with at least one s le available for analysis at any timepoint(s), compared to the overall original TREnd cohort. Fisher exact test was used to calculate p-values. *Denotes patients included in intention-to-treat population of TREnd, despite breach of eligibility criteria (discovered post-enrolment).
Publisher: American Society of Clinical Oncology (ASCO)
Date: 02-2022
DOI: 10.1200/JCO.2022.40.4_SUPPL.648
Abstract: 648 Background: People with cancer are at higher risk of serious illness and death from COVID-19 infection. We investigated the differences in COVID-19 vaccine uptake and attitudes in people with various solid organ and hematological malignancies. Methods: An online survey of adult patients with cancer attending eight health services across four states in Australia, was conducted from June to September 2021. Demographics, cancer history and vaccination status were recorded. Only completed surveys were analysed. Variables were compared with chi-squared and multivariable analysis using logistic regression. Vaccine hesitancy was assessed using the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford Vaccine Confidence and Complacency Scale, and the Monash Disease Vaccine Acceptance Scale. T-test analysis was used to examine relationships between the scales and groups. Results: There were 2997 evaluable responses 53.2% female, 61.8% from metropolitan areas, 27.5% with metastatic solid organ disease and 50.6% on current anti-cancer treatment. Patients with GI cancers comprised 13.5% (n = 405), compared with hematological 28.4%, breast 24.6%, genitourinary 14.1% and other cancer types 19.4%. Vaccination rates were significantly lower for respondents with GI cancers compared to other cancer types (71.6% v 79.3% p 0.001). Significant differences in the GI cancer population compared to all others were: more males ( p 0.001), lower level of education ( p= 0.001), fewer reporting English as first language ( p = 0.02) and shorter time since cancer diagnosis ( p 0.001). These remained significant after logistic regression. Among GI cancer respondents, factors associated with being vaccinated compared to unvaccinated included: older age ( p 0.001), higher education level ( p = 0.03) and English as first language ( p = 0.01). There was no significant difference in the scales measuring vaccine hesitancy, confidence and complacency, for the GI cancer population compared to other cancers. As expected, there were significant differences in all scales comparing vaccinated to unvaccinated respondents with GI cancers. Conclusions: In our large, contemporary survey, Australians with GI cancers report lower COVID-19 vaccine uptake compared with patients with other cancer types. We identified demographic and disease related characteristics that contribute to these differences. Interventions and targeted communication are required for people with GI cancers to maximise vaccination uptake in this medically vulnerable group.
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2019
DOI: 10.1158/1538-7445.SABCS18-P6-09-02
Abstract: Introduction: TK1 plays a crucial role in DNA synthesis and is a well-established marker of cell proliferation. We and others have previously described the potential role of TK1 activity (TKa) as predictive biomarker of response to endocrine therapy in HR+/HER2 negative metastatic breast cancer patients. TK1 synthesis is regulated by the E2F pathway, the target pathway of CDK4/6 inhibitors, and TKa has recently been reported as a potential circulating pharmacodynamic marker of CDK4/6 inhibition in breast cancer. However, modulations of TK1 levels and activity during palbociclib treatment and in the development of treatment resistance are unknown. Here, we report how TK1 expression and TKa are modulated in response to palbociclib in a panel of HR+ breast cancer cell lines: both palbociclib-sensitive (PDS) and with acquired resistance to (PDR). Material and methods: We used a panel of 7 PDR HR+ breast cancer models previously developed in our lab via chronic exposure of parental cells (MCF7, T47D, ZR75-1, BT474, MDAMB361 and two MCF7 endocrine resistant derivatives) to escalating doses of palbociclib, from a Starting Treatment Concentration (STC) of 50 nM or 350 nM according to the cell line, up to 1 μM. We analyzed gene expression profiles of PDS cells treated with drug vehicle (DMSO) as a control or palbociclib at STC for 3 days, and PDR cells grown with palbociclib 1 μM. Cell proliferation was assessed by methylene blue assay in MCF7 and BT474 PDS and PDR treated for 3, 6 and 9 days with DMSO, palbociclib STC and 1 μM. In parallel, TKa was measured in cell lysates at 3 days of treatment using the DiviTumTM assay (Biovica, Sweden). Results: Among E2F target genes, gene expression data demonstrated that TK1 was one of the most differentially expressed genes between PDR and PDS treated cells. In PDS cells compared to control, treatment with palbociclib resulted in reduced TK1 expression, with the HER2 positive models (BT474 and MDAMB361) showing the highest reduction. In PDR cells, TK1 expression was higher, but remained slightly inhibited compared to untreated PDS cells. TKa was significantly reduced in PDS cells treated with palbociclib for 3 days compared to vehicle (p& .05). TKa response to palbociclib was more dramatic in BT474 cells as compared to MCF7. As expected, palbociclib inhibited cell proliferation in PDS models, with a significant reduction observed only after 6 days of treatment, suggesting that TKa may be an early marker of growth inhibition in response to palbociclib. No significant alterations in TKa were observed in PDR cells, at any dose of palbociclib. Similarly, proliferation rate was not affected by palbociclib in PDR cells. Conclusions: TK1 expression and activity are regulated by palbociclib in HR+ breast cancer cell lines, particularly in HER2 positive models. Ongoing studies of TKa in patients treated with palbociclib will assess the role of TKa as a circulating biomarker for predicting and monitoring response to CDK4/6 inhibitors. Citation Format: Bonechi M, Migliaccio I, Benelli M, Romagnoli D, Bergqvist M, Mattsson K, Boccalini G, Capaccioli G, De Luca F, Galardi F, Biagioni C, Risi E, McCartney A, Rossi L, Osborne CK, Schiff R, De Angelis C, Guarducci C, Di Leo A, Malorni L. Effects of palbociclib on thymidine kinase-1 (TK1) in hormone receptor positive (HR+) breast cancer cell lines [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium 2018 Dec 4-8 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2019 (4 Suppl):Abstract nr P6-09-02.
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.CTRV.2018.04.012
Abstract: Breast cancer (BC) is a heterogeneous disease which has been characterised and stratified by many platforms such as clinicopathological risk factors, genomic assays, computer generated models, and various "-omic" technologies. Genomic, proteomic and transcriptomic analysis in breast cancer research is well established, and metabolomics, which can be considered a downstream manifestation of the former disciplines, is of growing interest. The past decade has seen significant progress made within the field of clinical metabolomic BC research, with several groups demonstrating results with significant promise in the setting of BC screening and biological characterisation, as well as future potential for prognostic metabolomic biomarkers.
Publisher: Research Square Platform LLC
Date: 26-02-2020
Abstract: Background Limited data are available on nab-paclitaxel in older breast cancer patients, with this population being under-represented in clinical trial. A weekly schedule is recommended, but there is a paucity of evidence regarding the optimal dose. We evaluated the efficacy of two different doses of weekly nab-paclitaxel, with a specific focus on their corresponding impact on patient function, in order to address the lack of data specifically relating to the older population. Methods EFFECT is an open-label, phase II trial wherein 160 women with advanced breast cancer aged ≥ 65 years were enrolled from 15 institutions within Italy. Patients were randomly assigned 1:1 to receive nab-paclitaxel 100 mg/m 2 (Arm A) or 125 mg/m 2 (Arm B) on days 1,8,15 on a 28-day cycle, as first-line treatment for advanced disease. The primary endpoint was event-free survival (EFS), wherein an event was defined as disease progression (PD), functional decline (FD) or death. Results After a median follow-up of 32.6 months, 140 events were observed in 158 evaluable patients. Median EFS was 8.2 months (90% CI, 5.9-8.9) in Arm A, versus 8.3 months (90% CI, 6.2-9.7) in Arm B. Progression-free survival, overall survival and response rates were similar in both groups. A higher percentage of dose reductions and discontinuations due to adverse events (AEs) was noted in Arm B. The most frequently reported non-hematological AEs were fatigue (grade [G] 2-3 toxicity occurrence in Arm A versus B: 43% and 51%, respectively) and peripheral neuropathy (G2-3 Arm A versus B: 19% and 38%, respectively). Conclusion The two weekly nab-paclitaxel regimens were comparable in all pre-specified outcomes. However, 100 mg/m 2 was significantly better tolerated with fewer neurotoxicity-related events, representing a more feasible dose to be recommended for older patients with advanced disease.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 06-2022
DOI: 10.1200/JCO.2022.40.16_SUPPL.TPS1112
Abstract: TPS1112 Background: The overexpression and/or lification of human epidermal growth factor receptor 2 (HER2) occurs in approximately 20% of breast cancers (BC) and is a major driver of tumor development and progression. This HER2 subtype confers aggressive tumor behavior and the HER2 receptor remains a valuable target for antibodies, bi-specifics, and antibody drug conjugates (ADC). With advances in targeted therapy, patients with HER2-positive breast cancer (HER2+ BC) may experience an improved prognosis, including survival. Novel HER2-targeted therapies are being investigated to overcome drug resistance and to help mitigate adverse events (e.g., cardiotoxicity). ARX788 is a next-generation ADC using a technology platform whereby a HER2 specific monoclonal antibody is conjugated with Amberstatin269 (AS269), a potent cytotoxic tubulin inhibitor. Site-specificity, high homogeneity, and stable covalent conjugation of ARX788 leads to its slow release and prolonged peak of serum pAF-AS269, which may contribute to the lower systemic toxicity and increased targeted delivery of payload to tumor cells at a lower effective dose compared to other HER2 ADCs. Clinical activity has been seen in Phase I HER2 breast and pan-tumor studies. Methods: Trial Design: ACE-Breast-03 (NCT04829604) is a global, phase 2 study designed to assess anticancer activity and safety of ARX788 in patients with metastatic HER2 positive breast cancer. Patients whose disease is resistant or refractory to T-DM1, and/or T-DXd, and/or tucatinib-containing regimens are eligible. Patients must have adequate organ function. Any brain metastases must be radiographically stable without steroid dependence. Efficacy will be assessed using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 by imaging every 6 weeks on study. Endpoints include objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), best overall response (BOR), duration of response (DOR), and time to response (TTR). The safety and tolerability profile will be evaluated. Blood s les will be collected at specified time points to determine serum concentrations of ARX788, total antibody, and metabolite pAF-AS269. Potential predictive and/or prognostic biomarkers at baseline and on-treatment will be analyzed for exploratory purposes. Descriptive statistics will be used to evaluate anticancer activity, safety, and tolerability. The study is currently recruiting patients. Please contact breast03trialinquiry@ambrx.com for additional information. Clinical trial information: NCT04829604.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2018
Publisher: MDPI AG
Date: 23-08-2022
Abstract: Background: Vaccination is the cornerstone of the global public health response to the COVID-19 pandemic. Excess morbidity and mortality of COVID-19 infection is seen in people with cancer. COVID-19 vaccine hesitancy has been observed in this medically vulnerable population, although associated attitudes and beliefs remain poorly understood. Methods: An online cross-sectional survey of people with solid organ cancers was conducted through nine health services across Australia. Demographics, cancer-related characteristics and vaccine uptake were collected. Perceptions and beliefs regarding COVID-19 vaccination were assessed using the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale and the Disease Influenced Vaccine Acceptance Scale-6. Results: Between June and October 2021, 2691 people with solid organ cancers completed the survey. The median age was 62.5 years (SD = 11.8 range 19–95), 40.9% were male, 71.3% lived in metropolitan areas and 90.3% spoke English as their first language. The commonest cancer diagnoses were breast (36.6%), genitourinary (18.6%) and gastrointestinal (18.3%) 59.2% had localized disease and 56.0% were receiving anti-cancer therapy. Most participants (79.7%) had at least one COVID-19 vaccine dose. Vaccine uptake was higher in people who were older, male, metropolitan, spoke English as a first language and had a cancer diagnosis for more than six months. Vaccine hesitancy was higher in people who were younger, female, spoke English as a non-dominant language and lived in a regional location, and lower in people with genitourinary cancer. Vaccinated respondents were more concerned about being infected with COVID-19 and less concerned about vaccine safety and efficacy. Conclusions: People with cancer have concerns about acquiring COVID-19, which they balance against vaccine-related concerns about the potential impact on their disease progress and/or treatment. Detailed exploration of concerns in cancer patients provides valuable insights, both for discussions with in idual patients and public health messaging for this vulnerable population.
Publisher: Apollo - University of Cambridge Repository
Date: 2022
DOI: 10.17863/CAM.87847
Publisher: Elsevier BV
Date: 03-2019
DOI: 10.1016/J.CTRV.2019.01.007
Abstract: Patients with luminal early breast cancer are at risk of relapse, even after five years of adjuvant endocrine therapy. To date, no biomarkers have been clinically validated to identify those patients at risk of late recurrence, who might benefit from extended adjuvant endocrine therapy. In recent decades, multiple clinical trials have tested the role of extending adjuvant endocrine therapies in patients with luminal disease. However, the data currently at our disposal are conflicting. This article reviews all the major trials concerning extended adjuvant endocrine regimens, and formulates some general conclusions and hypotheses of future study.
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2020
DOI: 10.1158/1538-7445.SABCS19-P5-06-11
Abstract: Introduction: Thymidine kinase is an established marker of cancer cell proliferation and its activity can be measured in blood. We and others have recently shown that baseline and dynamic evaluation of circulating thymidine kinase activity (TKa) during treatment gives prognostic and predictive information in patients with HR+, HER2-negative metastatic BC treated with endocrine therapy alone, as well as in the setting of CDK4/6 inhibition. However, there is limited data regarding the role of TKa as a prognostic biomarker in operable BC. Here we present a retrospective analysis of TKa in serum s les collected in a cohort of premenopausal women with operable BC enrolled in a phase III adjuvant multicenter clinical trial (NCT00201851). Materials and methods: Serum s les were available for 644 (87%) of participants prospectively enrolled in a randomized trial between 2003 and 2009 in South East Asia. All women were premenopausal, had stage II-IIIB HR+ operable BC and uniformly received bilateral surgical oophorectomy concurrent with mastectomy followed by tamoxifen alone for five years. Patients did not receive chemotherapy or targeted therapy pre- or post-operatively. Participants were randomized in the study according to the timing of surgery with respect to the phase of the menstrual cycle. Serum s les were collected preoperatively on the day of surgery. Serum TKa was measured using the ELISA-based DiviTum™ assay (Biovica, Sweden). TKa analysis was performed at a central laboratory, blind to clinical data. Baseline TKa values were correlated with clinico-pathological characteristics and clinical outcome. Clinical outcome was estimated using the Kaplan-Meier method. Results: The majority of patients had both estrogen and progesterone receptor positive tumors (94% and 92% respectively), 65% were HER2 negative (18% positive 17% unknown). Most had pT2 or pT3 disease (60% and 27% respectively), and more than half were node-positive (pN0 42%, pN1 27%, pN2 19%, pN3 11%, pNx 1%). The overall median TKa value was 65.4 Du/L. At five years, patients with a baseline TKa value below the median had a disease-free survival (DFS) rate of 75% versus 61% in those with a baseline over the median (HR 1.82, 95% CI 1.37-2.4, p& .001). Similar results were observed when women with HER2+ disease were excluded from analysis (HR 1.71, 95% CI 1.21-2.42, p=0.0025). Further prognostic precision was achieved when TKa values were ided by quartiles, with a 5 year DFS rate of 81%, 69%, 63% and 58% observed in the 1st, 2nd, 3rd and 4th quartiles respectively. After adjusting for major prognostic factors and randomization arm, TKa remained an independent marker. Conclusions: This study shows pre-operative TKa measured in serum is a strong prognostic marker in a large cohort of women with HR+ operable BC uniformly treated within a clinical trial. The notable rate of recurrence seen within this cohort of patients derived from non-high income countries may be mainly attributed to the relative degree of disease burden at diagnosis. TKa may be seen as a potential circulating marker of proliferation akin to tumor Ki67, which may provide useful prognostic information to guide adjuvant therapies. Citation Format: Luca Malorni, Ilenia Migliaccio, Chiara Biagioni, Lorenzo Rossi, Irene De Santo, Richard L Love, Amelia McCartney, Mattias Bergqvist, Martina Bonechi, Francesca De Luca, Francesca Galardi, Matteo Benelli, Dario Romagnoli, Emanuela Risi, Laura Biganzoli, Adriano Laudico, Nguyen Van Dinh, Angelo Di Leo. Serum thymidine kinase-1 activity (TKa) as a prognostic marker in premenopausal women with hormone receptor positive (HR+) operable breast cancer (BC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium 2019 Dec 10-14 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2020 (4 Suppl):Abstract nr P5-06-11.
Publisher: Elsevier BV
Date: 07-2023
Publisher: American Association for Cancer Research (AACR)
Date: 05-2020
DOI: 10.1158/1078-0432.CCR-19-3271
Abstract: Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both in vitro and in patients with ABC. Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor–positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the “To Reverse ENDocrine Resistance” (TREnd) trial (n = 46). Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients (n = 8) showing an increase—correlating with a worse outcome than those with decreased/stable TKa (n = 33 mPFS 3.0 vs 9.0 months P = 0.002). At T2, mTKa was 251 Du/L patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months P = 0.05). TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib.
Publisher: Cold Spring Harbor Laboratory
Date: 10-07-2022
DOI: 10.1101/2022.07.08.22277398
Abstract: Vaccination is the cornerstone of the global public health response to the COVID-19 pandemic. Excess morbidity and mortality of COVID-19 infection is seen in people with cancer. COVID-19 vaccine hesitancy has been observed in this medically vulnerable population, although associated attitudes and beliefs remain poorly understood. An online cross-sectional survey of people with solid organ cancers was conducted through nine health services across Australia. Demographics, cancer-related characteristics, and vaccine uptake were collected. Perceptions and beliefs regarding COVID-19 vaccination were assessed using the Oxford COVID-19 Vaccine Hesitancy Scale, the Oxford COVID-19 Vaccine Confidence and Complacency Scale, and the Disease Influenced Vaccine Acceptance Scale-6. Between June and October 2021, 2691 people with solid organ cancers completed the survey. Median age was 62.5 years ( SD =11.8 range 19-95), 40.9% were male, 71.3% lived in metropolitan areas, and 90.3% spoke English as their first language. The commonest cancer diagnoses were breast (36.6%), genitourinary (18.6%) and gastrointestinal (18.3%) 59.2% had localized disease and 56.0% were receiving anti-cancer therapy. Most participants (79.7%) had at least one COVID-19 vaccine dose. Vaccine uptake was higher in people who were older, male, metropolitan, spoke English as a first language, and had a cancer diagnosis for more than six months. Vaccine hesitancy was higher in people who were younger, female, spoke English as a non-dominant language and lived in a regional location, and lower in people with genitourinary cancer. Vaccinated respondents were more concerned about being infected with COVID-19 and less concerned about vaccine safety and efficacy. People with cancer have concerns about acquiring COVID-19, which they balance against vaccine-related concerns about the potential impact on their disease progress and/or treatment. Detailed exploration of concerns in cancer patients provides valuable insights, both for discussions with in idual patients and public health messaging for this vulnerable population.
Publisher: Elsevier BV
Date: 08-2017
DOI: 10.1016/J.BREAST.2017.06.021
Abstract: Luminal breast cancers demonstrate significant molecular and clinical heterogeneity, despite the commonality of shared expression of the estrogen receptor (ER). To date, no clinical trial has prospectively investigated the optimal chemotherapy regime according to luminal type, highlighting a paucity of data furthermore required to guide treatment decisions. Current methods of predicting advantage from adjuvant chemotherapy lack refinement and can over-estimate the risk of relapse, inevitably leading to a proportion of patients being unnecessarily exposed to chemotherapy. This paper will explore the evidence behind modalities which may add further value to existing known clinicopathological and molecular profiling techniques in predicting clinical benefit from chemotherapy. Adjuvant chemotherapy regime choice in the context of early luminal breast cancer types will be discussed, and areas for further research and debate identified.
Publisher: Hindawi Limited
Date: 16-07-2019
DOI: 10.1111/TBJ.13437
Abstract: Overall survival (OS), disease-free survival (DFS), and distant recurrence-free interval (DRFI) were evaluated from 169 patients diagnosed with early triple negative breast cancer. Overall, 5 and 10 years OS, DFS, and DRFI were 77% and 65% 60% and 46% and 74% and 73%, respectively. Forty-seven patients did not receive chemotherapy. A separate analysis was performed excluding those patients. In this subgroup, 5- and 10-year OS, DFS, and DRFI were 86% and 77% 68% and 54%, 77% both at 5 and 10 years. Prognosis is better than previously described adjuvant chemotherapy should be offered to fit elderly patients if clinically warranted.
Publisher: MDPI AG
Date: 20-01-2023
Abstract: Background: People with chronic illnesses have increased morbidity and mortality associated with COVID-19 infection. The influence of a person’s serious and/or comorbid chronic illness on COVID-19 vaccine uptake is not well understood. Aim: To undertake an in-depth exploration of factors influencing COVID-19 vaccine uptake among those with various serious and/or chronic diseases in the Australian context, using secondary data analysis of a survey study. Methods: Adults with cancer, diabetes and multiple sclerosis (MS) were recruited from 10 Australian health services to undertake a cross-sectional online survey (30 June to 5 October 2021) about COVID-19 vaccine uptake, vaccine hesitancy, confidence and complacency and disease-related decision-making impact. Free-text responses were invited regarding thoughts and feelings about the interaction between the participant’s disease, COVID-19, and vaccination. Qualitative thematic analysis was undertaken using an iterative process and representative verbatim quotes were chosen to illustrate the themes. Results: Of 4683 survey responses (cancer 3560, diabetes 842, and MS 281), 1604 (34.3%) included free-text comments for qualitative analysis. Participants who provided these were significantly less likely to have received a COVID-19 vaccination than those who did not comment (72.4% and 86.2%, respectively). People with diabetes were significantly less likely to provide free-text comments than those with cancer or MS (29.0%, 35.1% and 39.9%, respectively). Four key themes were identified from qualitative analysis, which were similar across disease states: (1) having a chronic disease heightened perceived susceptibility to and perceived severity of COVID-19 (2) perceived impact of vaccination on chronic disease management and disease-related safety (3) uncertain benefits of COVID-19 vaccine and (4) overwhelming information overload disempowering patients. Conclusions: This qualitative analysis highlights an additional layer of complexity related to COVID-19 vaccination decision making in people with underlying health conditions. Appreciation of higher susceptibility to severe COVID-19 outcomes appears to be weighed against uncertain impacts of the vaccine on the progression and management of the comorbid disease. Interactions by clinicians addressing in idual factors may alleviate concerns and maximise vaccine uptake in people with significant underlying health conditions.
Publisher: Elsevier BV
Date: 11-2019
Publisher: Springer Science and Business Media LLC
Date: 08-05-2020
DOI: 10.1038/S41416-020-0858-Y
Abstract: We describe a potential role for thymidine kinase-1, a general marker of cellular proliferation, to act as a prognostic biomarker in patients receiving CDK4/6 inhibitors for advanced hormone receptor-positive, HER2-negative breast cancer, with early data suggesting that it may also provide early indication of treatment response.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6530048
Abstract: AbstractPurpose: Thymidine kinase 1 (TK1) is downstream to the CDK4/6 pathway, and TK activity (TKa) measured in blood is a dynamic marker of outcome in patients with advanced breast cancer (ABC). This study explores TK1 as a biomarker of palbociclib response, both i in vitro /i and in patients with ABC. Experimental Design: Modulation of TK1 levels and activity by palbociclib were studied in seven estrogen receptor–positive breast cancer cell lines: sensitive (PDS) and with palbociclib acquired resistance (PDR). TKa was assayed in plasma obtained at baseline (T0), after one cycle (T1), and at disease progression on palbociclib (T2) in patients enrolled in the “To Reverse ENDocrine Resistance” (TREnd) trial ( i n /i = 46). Results: Among E2F-dependent genes, TK1 was significantly downregulated after short-term palbociclib. Early TKa reduction by palbociclib occurred in PDS but not in PDR cells. In patients, median TKa (mTKa) at T0 was 75 DiviTum units per liter (Du/L), with baseline TKa not proving prognostic. At T1, mTKa decreased to 35 Du/L, with a minority of patients ( i n /i = 8) showing an increase—correlating with a worse outcome than those with decreased/stable TKa ( i n /i = 33 mPFS 3.0 vs 9.0 months i P /i = 0.002). At T2, mTKa was 251 Du/L patients with TKa above the median had worse outcomes on post-study treatment compared with those with lower TKa (2.9 vs 8.7 months i P /i = 0.05). Conclusions: TK is a dynamic marker of resistance to palbociclib which may lead to early identification of patients in whom treatment escalation may be feasible. In addition, TKa may stratify prognosis in patients with acquired resistance to palbociclib. /
Publisher: Elsevier BV
Date: 03-2022
DOI: 10.1016/J.EJCA.2021.12.030
Abstract: Biomarkers for cyclin-dependent kinase 4/6 inhibitors, such as palbociclib, for patients with hormone receptor-positive/HER2-negative metastatic breast cancer are lacking. Thymidine kinase is a proliferation marker downstream of the cyclin-dependent kinase 4/6 pathway. We prospectively investigated the prognostic role of serum thymidine kinase activity (sTKa), in patients treated with Palbociclib + fulvestrant. PYTHIA was a phase II, single-arm, multicentre, trial that enrolled 124 post-menopausal women with endocrine-resistant hormone receptor-positive/HER2-negative metastatic breast cancer. Serum s les were collected pre-treatment (pre-trt n = 122), at day 15 of cycle 1 (D15 n = 108), during the one week-off palbociclib before initiating cycle 2 (D28 n = 108) and at end of treatment (n = 76). sTKa was determined centrally using Divitum®, a refined ELISA-based assay with a limit of detection of 20 Divitum Units (Du)/L. The primary study endpoint was progression-free survival, assessed for its association with pre- and on-treatment sTKa. Data from 122 women were analysed. Pre-treatment sTKa was not associated with clinical characteristics and moderately correlated with tissue Ki-67. Palbociclib + fulvestrant markedly suppressed sTKa levels at D15, with 83% of patients recording levels below limit of detection. At D28, sTKa showed a rebound in 60% of patients. At each timepoint, higher sTKa was associated with shorter progression-free survival (each p < 0.001), with the strongest effect at D15. STKa is an independent prognostic biomarker in patients treated with palbociclib. High pre-treatment sTKa and its incomplete suppression during treatment may identify patients with poorer prognosis and primary resistance. This warrants validation in prospective comparative trials. CLINICALTRIALS. NCT02536742 EudraCT 2014-005387-15.
Publisher: MDPI AG
Date: 28-04-2021
DOI: 10.3390/IJMS22094687
Abstract: Precision oncology is an emerging approach in cancer care. It aims at selecting the optimal therapy for the right patient by considering each patient’s unique disease and in idual health status. In the last years, it has become evident that breast cancer is an extremely heterogeneous disease, and therefore, patients need to be appropriately stratified to maximize survival and quality of life. Gene-expression tools have already positively assisted clinical decision making by estimating the risk of recurrence and the potential benefit from adjuvant chemotherapy. However, these approaches need refinement to further reduce the proportion of patients potentially exposed to unnecessary chemotherapy. Nuclear magnetic resonance (NMR) metabolomics has demonstrated to be an optimal approach for cancer research and has provided significant results in BC, in particular for prognostic and stratification purposes. In this review, we give an update on the status of NMR-based metabolomic studies for the biochemical characterization and stratification of breast cancer patients using different biospecimens (breast tissue, blood serum lasma, and urine).
Publisher: SAGE Publications
Date: 2019
Abstract: Chemotherapy added to anti-HER2 agents (H) is the treatment of choice in patients with HER2+ early breast cancer. However, HER2+ tumours are clinically and biologically heterogeneous, and treatment response varies significantly by hormone receptor (HR) status and molecular subtype. Predictive biomarkers are needed in this context. This study assessed whether an RB-1 loss of function gene signature (RBsig) is predictive of response to neoadjuvant chemotherapy in combination with trastuzumab, lapatinib or both, within the NeoALTTO trial. We collected RNA-sequencing data from pretreatment biopsies derived from the NeoALTTO trial. RBsig expression was computed retrospectively and correlated with pathological complete response (pCR) using receiver-operating characteristic (ROC) curves. The RBsig was dichotomised as High/Low in correspondence to the 25th percentile. Reported p values resulted from Fisher’s exact test. Of 455 NeoALTTO patients, 244 were eligible for this substudy (HR+ n = 129 HR− n = 115). Overall, pCR rate was significantly higher in patients with RBsig High tumours than those with RBsig Low (35% versus 18% respectively p = 0.01). The area under the ROC curve (AUC) was 0.60 (95% CI 0.52–0.67). A remarkably low pCR rate of 11% was seen in HR+/RBsig Low patients versus 28% in HR+/RBsig High. These results indicate RBsig may add valuable information to HER2 and HR expression, which may in turn inform treatment choices. HR+/HER2+/RBsig Low breast cancers exhibited the poorest pathological response following chemotherapy plus H. Accordingly, in such patients, endocrine therapy in combination with H and, possibly, a CDK4/6 inhibitor, may potentially prove to be a more effective treatment.
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2021
DOI: 10.1158/1538-7445.SABCS20-PS5-05
Abstract: Background: The CDK4/6 inhibitor palbociclib (P) plus fulvestrant (F) is approved for the treatment of patients (pts) with luminal metastatic breast cancer (MBC) progressed on prior endocrine therapy (ET). Despite clinical activity, a significant proportion of pts in this setting show primary resistance to P+F, with treatment failure within 3-6 months of initiation. To date there is no validated biomarker to identify such pts. Thymidine kinase 1 is a cancer proliferation marker downstream of the CDK4/6 pathway, whose activity can be measured in serum as a readout of tumour proliferation. Circulating thymidine kinase activity (TKa) is a potential prognostic and monitoring marker in pts treated with ET alone or in combination with P for MBC. However, the prognostic value of early changes in TKa during P+F treatment and its role in identifying pts with primary resistance are not yet defined. Here we prospectively investigated the role of serum TKa measured at different timepoints in pts treated with P+F within the PYTHIA trial (IBCSG 53-14/BIG 14-04 NCT02536742), a downstream trial of the AURORA platform (BIG 14-01 NCT02102165). Methods: PYTHIA is a biomarker discovery phase II trial including pts (Aug ‘16 to Jun ’19) with ET-resistant luminal MBC who received P+F at standard schedule and dose with 3-monthly imaging. Serum s les were collected at baseline (D0 n=122), on-treatment at day 11-16 of cycle 1 (D15 n=108), and during the one week off P before initiating cycle 2 (D28: Day 24-37 of Cycle 1 n=108). TKa was measured with DiviTum®, a refined ELISA-based assay. Complete TKa response (CTR) was defined as TKa below the limit of detection (LOD 20 Du/L) at D15. Cox models evaluated association of log-transformed TKa measurements with progression-free survival (PFS from initiation of therapy until progression by RECIST criteria or death). Kaplan-Meier method estimated median, 3 and 6 months (95% CI) PFS in groups of patients defined by dichotomizing TKa as “high” or “low” at the median or by CTR. A s le size of 120 provided 80% power to detect a hazard ratio of 2.0 for biomarker with 30-50% prevalence (two-sided α=0.05) after ≥80 events. Results: A total of 122 pts were enrolled. About half had received one prior line of ET for MBC, and 18% had received one prior line of chemotherapy. 48% had visceral metastases and 31% had bone-only disease. TKa at D0 was not associated with clinical characteristics. Median TKa (mTKa) at D0 was 87 Du/L. Overall, 82 pts experienced progression, with a median PFS (mPFS) of 11 months (95% CI: 8.6 - 16). P+F dramatically suppressed mTKa levels at D15, with 90/108 (83%) pts achieving CTR. At D28, TKa showed some rebound in most pts. At each timepoint, higher TKa was significantly and consistently associated with shorter PFS (each p& .001). The effect of TKa on PFS remained statistically significant after adjusting for clinical variables. At 6 months, the largest difference between PFS probabilities was observed between patients with CTR versus no CTR at D15. Conclusions: TKa is an independent prognostic biomarker in pts treated with P+F. High baseline TKa and incomplete suppression of TKa during treatment may identify pts with poor prognosis and primary resistance to P+F. TKa may represent a novel biomarker to select pts for alternative treatment modalities. These results warrant further investigation in prospective comparative trials. TimepointBaseline (D0)D151D28TK median value (Du/L) (range)87 (& - 14,510)& (& - 7,060)52 (& - 3,533)S le sizeHigh TKa611854Low TKa619054mPFS (months) (95% CI)High TKa7.4 m (5.5 - 8.7)4.9 m (2.8 - 5.9)8.3 m (5.6 - 11)Low TKa17.0 m (14 - NR2)16.0 m (11 - 30)19.0 m (17 - NR2)PFS at 3 months(95% CI)High Tka79% (43% - 68%)61% (42% - 88%)78% (67% - 90%)Low TKa93% (87% - 100%)92% (87% - 98%)96% (91% - 100%)PFS at 6 months(95% CI)High TKa54% (43% - 68%)17% (6% - 47%)56% (44% - 71%)Low TKa88% (81% - 97%)85% (78% - 93%)92% (86% - 100%)1For D15 High/Low TKa correspond to no CTR/CTR 2 NR = not reached Citation Format: Luca Malorni, Svitlana Tyekucheva, Florentine S Hilbers, Michail Ignatiadis, Patrick Neven, Marco Colleoni, Stéphanie Henry, Alberto Ballestrero, Andrea Bonetti, Guy Jerusalem, Konstantinos Papadimitriou, Antonio Bernardo, Francois Duhoux, Iain MacPherson, Alastair Thomson, David Mark Davies, Mattias Bergqvist, Matteo Benelli, Amelia McCartney, Heidi De Swert, Barbara Ruepp, Manuela Rabaglio, Rudolf Maibach, Martine Piccart, Meredith M Regan. Serum thymidine kinase activity in patients with luminal metastatic breast cancer treated with palbociclib and fulvestrant within the PYTHIA trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium 2020 Dec 8-11 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2021 (4 Suppl):Abstract nr PS5-05.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2021
DOI: 10.1200/JCO.2021.39.15_SUPPL.1038
Abstract: 1038 Background: ARX788 is a site-specific, homogeneous, and highly stable ADC. The payload AS269 is conjugated to the synthetic amino acids para-acetylphenylalanine (pAF) in a humanized anti-HER2 mAb. ARX788 demonstrated promising activity in HER2-positive, HER2-low, and T-DM1 resistant tumors in preclinical studies. Here we present the phase 1 clinical data evaluating the safety, antitumor activity, and PK of ARX788 in advanced solid tumors. Methods: The standard 3+3 design (0.33 - 1.5 mg/kg Q3W or Q4W) is used to determine the MTD and/or RP2D in two phase 1 studies in HER2-positive solid tumors in U.S. and Australia (ACE-Pan tumor-01) and in HER2-positive breast cancers in China (ACE-Breast-01). The efficacy endpoints include ORR and DCR. Intensive PK s ling in first 3 cycles is performed to characterize serum PK profiles of ARX788, total Ab, and pAF-AS269. Results: 69 and 34 heavily pretreated patients received ARX788 monotherapy in the ACE-Breast-01 (median 6 prior lines of therapy) and ACE-Pan tumor-01 trial (including breast, gastric/GEJ, NSCLC, ovarian, urothelial, biliary track, endometrial, and salivary gland cancer) respectively. Dose escalation for both studies have been completed with no DLT reported. MTD has not been reached. ARX788 was generally well tolerated with most AEs being grade 1 or 2. The most common grade AEs include ocular AEs (5.7 %) and pneumonitis (4.3%) in the ACE-Breast-01 trial pneumonitis (2.9%) and fatigue (2.9%) in the ACE-Pan tumor-01 trial. Low systemic toxicities in terms of the incidence rate and grade (as shown in table). No treatment-related death. In the 1.5 mg/kg cohort, ORR was 74% (14/19) and 67% (2/3) for ACE-Breast-01 and ACE-Pan tumor-01, respectively. DCR was 100%. Median DOR or median PFS has not been reached. PK profiles for total antibody and ARX788 were generally comparable across all dose levels. Mean T1/2 for ARX788 and total antibody had approximately 100 hours at the dose of 1.5 mg/kg. Serum pAF-AS269 concentrations peaked with a median time of 168 h. Serum exposure of pAF-AS269 was low with the Cmax and AUC at cycle 1 being approximately 0.1% and 0.18% of those for ARX788 on a molar basis, respectively. Conclusions: High stability of ARX788 and low serum exposure of pAF-AS269 may underlie the low systemic toxicity, which differentiates it from other ADCs. Clinical trial information: NCT032550070 .[Table: see text]
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2018
No related grants have been discovered for Amelia McCartney.