ORCID Profile
0000-0003-0944-4807
Current Organisation
Royal Australasian College of Physicians
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Publisher: Wiley
Date: 30-08-2001
DOI: 10.1046/J.1445-5994.2001.00078.X
Abstract: In severe aplastic anaemia, the treatment of choice for young patients with a human leucocyte antigen-matched sibling is now established as allogeneic bone marrow transplantation (BMT). In older patients and in those without a matched sibling donor, immunosuppressive therapy is the usual first option. 'Alternative' marrow donors are emerging as an option for those without a matched sibling donor. To review 10 years of local experience in treating severe aplastic anaemia with BMT and immunosuppressive therapy with emphasis on long-term outcomes. A retrospective analysis was performed of all patients with severe aplastic anaemia presenting to the Royal Brisbane and Royal Children's Hospitals between 1989 and 1999. Data were abstracted regarding patient demographics, pretreatment characteristics and outcome measures, including response rates, overall survival and long-term complications. Twenty-seven consecutive patients were identified, 12 treated with immunosuppression alone and 15 with BMT. In these two groups, transfusion independence was attained in 25% and 100%, respectively, with overall survival being 36% and 100%, respectively. Those treated with immunosuppression were significantly older (median 41.5 versus 22 years, P = 0.008). Long-term survivors of either treatment had extremely low morbidity. Three patients carried pregnancies to term post-transplant. Three patients received alternative donor BMT with correspondingly excellent survival. Patients treated with allogeneic BMT for severe aplastic anaemia enjoyed extremely good long-term survival and minimal morbidity. Patients treated with immunosuppressive therapy had a poorer outcome reflecting their older age and different usage of therapies over the past decade. Optimal treatment strategies for severe aplastic anaemia remain to be determined.
Publisher: Elsevier BV
Date: 2020
Publisher: Wiley
Date: 03-04-2018
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2016
DOI: 10.1158/1538-7445.SABCS15-P4-14-12
Abstract: Background: Intravenous (IV) trastuzumab has proven clinical benefits in patients (pts) with human epidermal growth factor receptor 2 (HER2)-positive breast cancer (BC). The use of pertuzumab, which targets HER2 through an independent epitope to that of trastuzumab, in combination with IV trastuzumab and docetaxel has shown improved efficacy with acceptable toxicity in metastatic (m) BC. Subcutaneous (SC) and IV trastuzumab formulations have shown comparable efficacy. This study aimed to assess the safety, tolerability, and efficacy of combining IV pertuzumab with SC trastuzumab and a taxane, as 1st-line therapy in pts with HER2+ mBC, a combination for which results have not previously been reported. Here we present demographics and interim safety data. Methods: This is an open-label, multicentre, phase IIIb study. The primary objective was the safety and tolerability of IV pertuzumab with SC trastuzumab and investigator's choice of taxane. Pts aged ≥18 years with confirmed HER2-positive [IHC3+ or ISH+] mBC with at least one measurable lesion and/or non-measurable disease according to RECIST version 1.1 and ECOG performance status (PS) 0-2 were included. Pts received IV pertuzumab every 3 weeks (loading dose=840 mg subsequent doses=420mg) combined with SC trastuzumab at 600mg/5mL every 3 weeks and the investigator's choice of taxane (docetaxel, paclitaxel, or nab-paclitaxel). Treatment continued until disease progression, unacceptable toxicity, or consent was withdrawn, whichever occurred first. The incidence and severity of adverse events (AEs), serious (S) AEs and AEs leading to premature discontinuation of study treatment were analyzed. Results: The planned 50 pts have been recruited from 12 centres mean age 53 (SD-12.0) years the majority white (84%), ECOG PS 0 (n=33) and PS 1 (n=15). 98% were females 61% post-menopausal. Taxanes of choice were nab-paclitaxel (n=36), docetaxel (n=13) and paclitaxel (n=1). Any grade AEs (n=627) were reported in 100% pts majority grade 1-2, the most common being diarrhoea, fatigue, peripheral neuropathy, alopecia, nausea, rash, headache and vomiting. Grade 3+ AEs (n=54) were reported in 52% pts, most commonly neutropenia (10%), febrile neutropenia (8%) and diarrhoea (6%). SAEs (n=36) were reported in 48% pts most commonly pyrexia (14%), febrile neutropenia (8%), neutropenia (4%), pulmonary embolism (4%) and cellulitis (4%). Five AEs of suspected cardiac disorders were reported in 4 pts (atrial fibrillation, cardiomyopathy, myocardial ischemia, palpitations and ejection fraction decreased). AEs leading to study drug discontinuation (n=3) were reported in 3 pts (LVEF decreased, syncope and blister). AEs leading to chemotherapy discontinuation (n=14) were reported in 20% pts. Conclusion: We report the first data on the use of pertuzumab with SC trastuzumab. The observed safety profile is consistent with that previously reported in the CLEOPATRA (Baselga, et al. NEJM 2012 :109-19), PERUSE [Bachelot, et al. JCO 2014 :5s(abstr#548)] and HannaH (Ismael, et al. Lancet Oncol 2012 :869-78) studies, with no unexpected safety signals. Clinical trial information:NCT02019277. Citation Format: Woodward N, De Boer RH, Redfern A, White M, Young J, Truman M, Beith J. Interim results from the first open-label, multicenter, phase IIIb study investigating the combination of pertuzumab with subcutaneous trastuzumab and a taxane in patients with HER2-positive metastatic breast cancer (SAPPHIRE). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2016 (4 Suppl):Abstract nr P4-14-12.
Publisher: Oxford University Press (OUP)
Date: 19-03-2018
DOI: 10.1093/IJE/DYY016
Publisher: Elsevier BV
Date: 07-2021
Publisher: Springer Science and Business Media LLC
Date: 10-06-2020
Publisher: Wiley
Date: 06-2016
DOI: 10.1111/AJCO.12500
Abstract: Treatment with pertuzumab-trastuzumab-taxane combinations has become the international standard of care for patients with HER2-positive metastatic breast cancer. In this paper we discuss the practicalities of treating patients with this combination with a particular focus on treatment in the Australian setting. An expert panel was convened to discuss practical aspects for use of pertuzumab in the Australian clinical setting. The findings of this panel are reported in this article. The combination of pertuzumab-trastuzumab-docetaxel has established efficacy in patients with HER2-positive metastatic breast cancer, prolonging progression-free and overall survival compared to trastuzumab-taxane combinations. In Australia, combinations of pertuzumab and trastuzumab with docetaxel or paclitaxel are reimbursed. Management of treatment related side-effects such as diarrhea, febrile neutropenia and neuropathy typically include dose reduction or switching taxane. Specific patients with poorer tolerance of chemotherapy such as the elderly or those from Asian backgrounds may require particular management strategies. The advent of targeted therapies for women with metastatic HER2-positive breast cancer has markedly improved survival. Combinations of pertuzumab-trastuzumab and a taxane are the standard of care in patients with good performance status. Given prolongation of survival and the importance of quality of life endpoints, the treatment paradigm for patients with metastatic HER2-positive breast cancer is changing rapidly. Careful management of toxicities is required, and dose reduction or switching taxane may be necessary. Further research is required on the efficacy of pertuzumab combinations in patients with brain metastases, and on those who relapse quickly following adjuvant therapy.
Publisher: Oxford University Press (OUP)
Date: 21-10-2019
Abstract: Talazoparib is a poly(adenosine diphosphate-ribose) polymerase inhibitor that causes death in cells with breast cancer susceptibility gene 1 or 2 (BRCA1/2) mutations. EMBRACA (NCT01945775) was a randomized phase III study comparing efficacy, safety, and patient-reported outcomes (PROs) of talazoparib (1 mg) with physician’s choice of chemotherapy (PCT: capecitabine, eribulin, gemcitabine, vinorelbine) in locally advanced or metastatic breast cancer with a germline BRCA1/2 (gBRCA1/2) mutation. Prespecified patient subgroups were analyzed for progression-free survival, objective response, clinical benefit, duration of response, and safety. PROs were evaluated in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) or triple-negative breast cancer (TNBC) subgroups. Of 431 patients, 287 were randomly assigned to talazoparib and 144 to PCT. Prespecified subgroup analyses showed prolonged progression-free survival with talazoparib (HR+/HER2−: hazard ratio = 0.47, 95% confidence interval = 0.32 to 0.71 TNBC: hazard ratio = 0.60, 95% confidence interval = 0.41 to 0.87) and greater objective response rate (odds ratio = 1.97 to 11.89), clinical benefit rate (odds ratio = 2.05 to 7.77), and duration of response with talazoparib in all subgroups. PROs in HR+/HER2− and TNBC subgroups showed consistent overall improvement and delay in time to definitive clinically meaningful deterioration with talazoparib vs PCT. Across subgroups, common adverse events included anemia, fatigue, and nausea with talazoparib and neutropenia, fatigue, and nausea with PCT. Seven patients (2.4%) receiving talazoparib had grade II alopecia and 22.7% had grade I alopecia. Across all patient subgroups with gBRCA-mutated advanced breast cancer, talazoparib demonstrated clinically significant superiority in outcomes compared with PCT.
Publisher: Springer Science and Business Media LLC
Date: 11-2018
Publisher: Wiley
Date: 14-04-2021
DOI: 10.1111/AJCO.13576
Abstract: Review of utilization and efficacy of eribulin in Australian metastatic breast cancer (MBC) patients. Retrospective review of consecutive MBC patients treated with eribulin in tertiary Australian BC centers. Key inclusion criteria included eribulin administration in nonclinical trial setting from October 2014 onwards, known duration of MBC systemic treatments administered and known follow‐up date after eribulin. Cox regression model was used to assess survival. Study population comprised 266 patients from eight centers treated between October 2014 and May 2018. Median age at time of MBC diagnosis was 54 years with 18% of patients having de novo MBC. Seventy‐six percent had hormone receptor positive (HRp) disease, 19% triple negative (TN) and 5% HER2‐positive. CNS involvement was present in 36% of patients. Eribulin was most frequently given as third‐line chemotherapy (36%), with no prior anthracycline exposure in 14% of total population. Eribulin was given more frequently as ≤third‐line chemotherapy than third‐line in patients with TN disease, ≥ two metastatic sites or CNS disease. Median overall survival (OS) from eribulin administration was 9.2 (95% CI [8.0, 10.3]) months. Similar efficacy was demonstrated for eribulin when given in the first‐line to beyond the fifth line of chemotherapy in all subtypes of MBC.
Publisher: Oxford University Press (OUP)
Date: 25-05-2017
DOI: 10.1093/NOP/NPW025
Abstract: In patients with recurrent glioblastoma, the benefit of bevacizumab beyond progression remains uncertain. We prospectively evaluated continuing or ceasing bevacizumab in patients who progressed while on bevacizumab. CABARET, a phase II study, initially randomized patients to bevacizumab with or without carboplatin (Part 1). At progression, eligible patients underwent a second randomization to continue or cease bevacizumab (Part 2). They could also receive additional chemotherapy regimens (carboplatin, temozolomide, or etoposide) or supportive care. Of 120 patients treated in Part 1, 48 (80% of the anticipated 60-patient s le size) continued to Part 2. Despite randomization, there were some imbalances in patient characteristics. The best response was stable disease in 7 (30%) patients who continued bevacizumab and 2 (8%) patients who stopped receiving bevacizumab. There were no radiological responses. Median progression-free survival was 1.8 vs 2.0 months (bevacizumab vs no bevacizumab hazard ratio [HR], 1.08 95% CI, .59–1.96 P = .81). Median overall survival was 3.4 vs 3.0 months (HR, .84 95% CI, .47–1.50 P = .56 and HR .70 95% CI .38–1.29 P = .25 after adjustment for baseline factors). Quality-of-life scores did not significantly differ between arms. While the maximum daily steroid dose was lower in the continuation arm, the difference was not statistically significant. Patients who continued bevacizumab beyond disease progression did not have clear survival improvements, although the study was not powered to detect other than very large differences. While these data provide the only randomized evidence related to continuing bevacizumab beyond progression in recurrent glioblastoma, the small s le size precludes definitive conclusions and suggests this remains an open question.
Publisher: Elsevier BV
Date: 10-2018
DOI: 10.1016/J.CLBC.2018.04.016
Abstract: Maintaining the relative dose intensity (RDI) of adjuvant chemotherapy at ≥ 85% has been associated with improved treatment outcomes in early-stage breast cancer (ESBC). Increasing evidence has suggested that patients aged ≥ 65 years can maintain the optimal RDI for standard chemotherapy regimens. The present study investigated the RDI of newer adjuvant chemotherapy regimens in this demographic. We retrospectively analyzed the data from 281 patients aged ≥ 65 years with a diagnosis of ESBC who had received adjuvant chemotherapy across 3 sites in Queensland, Australia from 2010 to 2015. The primary endpoint was the proportion of patients who had received an RDI of ≥ 85%. The median age at diagnosis was 68 years (range, 65-85 years), with 36.3% aged > 70 years. The patient characteristics included tumor stage T3 or T4 in 17% and node-positive disease in 60%. The common chemotherapy regimens included docetaxel/cyclophosphamide (23%), 5-fluorouracil/epirubicin/cyclophosphamide plus docetaxel or paclitaxel (17%) Adriamycin/cyclophosphamide/weekly paclitaxel (38%) and docetaxel/carboplatin/trastuzumab (11%). Primary (15%) and secondary (54%) granulocyte colony-stimulating factor (G-CSF) was used. An RDI of ≥ 85% was achieved in 63% of the patients. Significant associations were noted between a reduced RDI and age ≥ 70 years (P < .001), Charlson comorbidity index ≥ 1 (P = .043), initial dose reductions (P = .01), secondary G-CSF use (P = .45), hospital admission (P < .001), and febrile neutropenia (P = .007). Treatment-related toxicities were the most common reason for noncompletion, with high rates of hospital admissions (46%) and febrile neutropenia (22%). Our findings suggest that patients aged ≥ 65 years with ESBC can maintain an optimal RDI with modern chemotherapy regimens. Appropriate geriatric assessment and the use of supportive measures such as G-CSF could better assist select groups to maintain an optimal dose intensity.
Publisher: Springer Science and Business Media LLC
Date: 16-05-2020
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.AHJ.2009.05.031
Abstract: Trastuzumab prolongs survival in patients with human epidermal growth factor receptor type 2-positive breast cancer. Sequential left ventricular (LV) ejection fraction (EF) assessment has been mandated to detect myocardial dysfunction because of the risk of heart failure with this treatment. Myocardial deformation imaging is a sensitive means of detecting LV dysfunction, but this technique has not been evaluated in patients treated with trastuzumab. The aim of this study was to investigate whether changes in tissue deformation, assessed by myocardial strain and strain rate (SR), are able to identify LV dysfunction earlier than conventional echocardiographic measures in patients treated with trastuzumab. Sequential echocardiograms (n = 152) were performed in 35 female patients (51 +/- 8 years) undergoing trastuzumab therapy for human epidermal growth factor receptor type 2-positive breast cancer. Left ventricular EF was measured by 2- and 3-dimensional (2D and 3D) echocardiography, and myocardial deformation was assessed using tissue Doppler imaging and 2D-based (speckle-tracking) strain and SR. Change over time was compared every 3 months between baseline and 12 months. There was no overall change in 3D-EF, 2D-EF, myocardial E-velocity, or strain. However, there were significant reductions seen in tissue Doppler imaging SR (P < .05), 2D-SR (P < .001), and 2D radial SR (P or =1 SD in 2D longitudinal SR was seen in 18 (51%) patients 13 (37%) had a similar drop in radial SR. Of the 18 patients with reduced longitudinal SR, 3 had a concurrent reduction in EF > or =10%, and another 2 showed a reduction over 20 months follow-up. Myocardial deformation identifies preclinical myocardial dysfunction earlier than conventional measures in women undergoing treatment with trastuzumab for breast cancer.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-01-2016
DOI: 10.1200/JCO.2016.34.3_SUPPL.157
Abstract: 157 Background: Aromatase inhibitor-associated musculoskeletal symptoms (AIMSS) are experienced by a significant number of women on adjuvant aromatase inhibitors for breast cancer. These symptoms can result in therapy noncompliance and there is no accepted standardised treatment. We believe that this is the first systematic review to consider the evidence for all pharmacological and non-pharmacological interventions in the treatment of AIMSS. Methods: We conducted a systematic search in PubMed, EMBASE, CINAHL and CENTRAL. Clinical trials and observational studies for all potential pharmacological and non-pharmacological interventions were included. Two reviewers screened the results and extracted the relevant data. Risk of bias for the full papers were assessed using JADAD or a modified Newcastle Ottawa score, with conference abstracts and letters to the editor excluded from this process. Results: Of 1260 records being identified, 887 unique citations were screened with 93 full text papers retrieved for assessment, and 37 selected for inclusion. We identified 9 pharmacological interventions (RCT = 3, pre-post = 4, cohort = 2) and 28 non-pharmacological interventions (RCT/CCT = 16, pre-post = 8, cohort = 3). The largest number of studies were for various exercise interventions (n = 7) with the largest trial showing a 29% decrease in worst joint pain scores compared to the control (2%, p 0.001). The highest number of RCTs was for acupuncture (n = 5), the majority of which showed a significant benefit with both real and sham acupuncture. Other single RCTs showing benefit include the use of testosterone, calcitonin and etoricoxib. No study adequately controlled for contamination bias from extraneous variables of both pharmacological and non-pharmacological interventions. Conclusions: Given that pharmacological treatment is often recommended for AIMSS, it is surprising that there is limited published evidence for its use. Although the interventions being used appear tolerable with minimal adverse effects, the current level of evidence is low, and additional large RCTs with more rigorous controlling for contamination from other interventions are required to confirm some of the reported promising results.
Publisher: Elsevier BV
Date: 10-2016
Publisher: Springer Science and Business Media LLC
Date: 03-06-2020
DOI: 10.1038/S41586-020-2338-1
Abstract: High blood cholesterol is typically considered a feature of wealthy western countries 1,2 . However, dietary and behavioural determinants of blood cholesterol are changing rapidly throughout the world 3 and countries are using lipid-lowering medications at varying rates. These changes can have distinct effects on the levels of high-density lipoprotein (HDL) cholesterol and non-HDL cholesterol, which have different effects on human health 4,5 . However, the trends of HDL and non-HDL cholesterol levels over time have not been previously reported in a global analysis. Here we pooled 1,127 population-based studies that measured blood lipids in 102.6 million in iduals aged 18 years and older to estimate trends from 1980 to 2018 in mean total, non-HDL and HDL cholesterol levels for 200 countries. Globally, there was little change in total or non-HDL cholesterol from 1980 to 2018. This was a net effect of increases in low- and middle-income countries, especially in east and southeast Asia, and decreases in high-income western countries, especially those in northwestern Europe, and in central and eastern Europe. As a result, countries with the highest level of non-HDL cholesterol—which is a marker of cardiovascular risk—changed from those in western Europe such as Belgium, Finland, Greenland, Iceland, Norway, Sweden, Switzerland and Malta in 1980 to those in Asia and the Pacific, such as Tokelau, Malaysia, The Philippines and Thailand. In 2017, high non-HDL cholesterol was responsible for an estimated 3.9 million (95% credible interval 3.7 million–4.2 million) worldwide deaths, half of which occurred in east, southeast and south Asia. The global repositioning of lipid-related risk, with non-optimal cholesterol shifting from a distinct feature of high-income countries in northwestern Europe, north America and Australasia to one that affects countries in east and southeast Asia and Oceania should motivate the use of population-based policies and personal interventions to improve nutrition and enhance access to treatment throughout the world.
Publisher: BMJ
Date: 17-04-2017
DOI: 10.1136/JCLINPATH-2016-204304
Abstract: Progesterone receptor (PR) expression is prognostic in early stage breast cancer. There are several reports of discordant expression between primary tumour and axillary lymph node (ALN) metastasis expression of oestrogen receptor (ER) and PR. We sought to determine whether expression of these biomarkers in the synchronous ALN metastases of ER positive (+), HER2 negative (−) breast cancer could provide more accurate prognostic information. The retrospective cohort included 229 patients from a single institution with ER+, HER2− breast cancer who had synchronous ALN metastatic disease (2005–2014). PR expression was correlated with relapse-free survival, and subset analysis was performed for patients who received adjuvant tamoxifen or an aromatase inhibitor. One patient had an ER+ primary tumour, which was ER− in the ALN metastasis. 27 (11.3%) were PR− in the primary tumour and 56 (23.6%) in the ALN metastasis. The predominant change was from PR+ in the primary tumour to PR− in the lymph node. Absence of PR expression in the ALN was significantly associated with relapse however, this was not the case in the primary tumour. In a subset analysis of patients taking adjuvant endocrine therapy, poorer prognosis was limited to those with PR− metastases on tamoxifen (HR=5.203, 95% CI 1.649 to 16.416, p=0.005). No significant prognostic effect of PR− metastases in patients taking aromatase inhibitors was seen (HR=1.519, 95% CI 0.675 to 3.418, p=0.312). Evaluation of PR expression in ALN metastasis may enable prediction of patients who are less likely to benefit from adjuvant tamoxifen. This study should be replicated in other cohorts.
Publisher: Elsevier BV
Date: 11-2020
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2019
DOI: 10.1158/1538-7445.SABCS18-P6-18-12
Abstract: Background: Talazoparib (TAL) prevents DNA damage repair by inhibiting poly (ADP-ribose) polymerase (PARP) enzymes and trapping PARP on DNA, resulting in cell death in BRCA1/2-mutated cells. Methods: EMBRACA is an open-label, randomized, 2-arm phase 3 trial in which efficacy and safety of TAL (1 mg/d) were compared with physician's choice of therapy (PCT capecitabine, eribulin, gemcitabine, vinorelbine) in patients (pts) with locally advanced or metastatic breast cancer (ABC) and a germline BRCA mutation (gBRCAm). Outcomes were assessed by region of the world (North America [NA] Europe [EU] rest of world [ROW]). Progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR) at 24 wks were assessed safety was also assessed. Results: 431 pts were randomized 2:1. Pt characteristics were well balanced, although a higher percentage of pts in ROW had more severe disease (eg, triple-negative breast cancer [TNBC], Disease-free interval [DFI]& mo, more distant metastases, more disease sites) and were on average younger than pts in NA/EU. TAL provided improvement in PFS, ORR, and CBR in all regions vs PCT. The most common toxicities with TAL included anemia, neutropenia, thrombocytopenia, fatigue, and nausea for all regions. Alopecia was less frequent with TAL in EU/ROW. Serious adverse events for pts receiving TAL were more frequent in EU than NA/ROW. Incidences of adverse events associated with permanent treatment discontinuation in pts receiving TAL were low in all regions and generally lower than for PCT. Table 1CategoryNA* (N=156)EU* (N=190)ROW* (N=85)Mean age, years49.049.244.2Race, % White76.971.152.9Black5.8-3.5Asian5.8-42.4Not reported-27.4-TNBC, %424447BRCA1**, %414748BRCA2**, %595352DFI& mo, %313444Distant metastases, %949397≥3 disease sites, %474049PFS, (hazard ratio [HR] [95% CI]) P value0.46 [0.29-0.74] P=.00090.52 [0.33-0.80] P& .0030.57 [0.31-1.07] P=.08ORR (odds ratio [OR] [95% CI]) P value5.54 [2.4-16.1] P& .00013.75 [1.57-9.87] P=.0016.7 [1.61-28.39] P=.001CBR (OR [95% CI]) P value4.71 [2.20-10.57] P& .00013.39 [1.56-7.36] P=.00075.70 [1.70-17.13] P=.002Hematologic AEs, % Anemia50.558.642.6Neutropenia31.332.346.3Thrombocytopenia28.322.635.2Nonhematologic AEs, % Fatigue59.643.650.0Nausea47.545.957.4Headache32.330.837.0Alopecia34.320.320.4Serious adverse events, %25.340.622.2Treatment discontinuation, n/N, (%) TAL7/99 (7.1)12/133 (9.0)3/54 (5.6)PCT7/43 (16.3)3/54 (5.6)2/29 (6.9)AE, adverse event CI, confidence interval *NA (United States) EU (Belgium, France, Germany, Ireland, Italy, Poland, Spain, United Kingdom, Russia, Ukraine, Israel) ROW (Brazil, Korea, Australia, Taiwan).**Central laboratory. Conclusions: In pts with gBRCAm ABC, TAL demonstrated significant improvements in clinical outcomes compared with PCT regardless of the region of the world in which they lived. However, slight differences among the regions in baseline characteristics were noted, possibly due to regional variation in diagnosis and detection of gBRCAm ABC as well as different treatment paradigms for metastatic breast cancer. Funding: Me ation LLC, acquired by Pfizer. Citation Format: Mina L, Lee K-H, Gonçalves A, Woodward N, Hurvitz SA, Diab S, Yerushalmi R, Goodwin A, Moreira Costa Zorzetto M, Kim S-B, Czibere A, Tudor IC, Gauthier E, Litton JK, Ettl J. EMBRACA: Efficacy and safety of talazoparib or physician's choice of therapy in patients with advanced breast cancer and a germline BRCA1/2 mutation: A regional analysis [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 P6-18-12.
Publisher: Elsevier BV
Date: 12-2022
DOI: 10.1016/J.ANNONC.2022.09.159
Abstract: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68 98.5% confidence interval (CI) 0.47-0.97 P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals.
Publisher: Elsevier BV
Date: 02-2020
Publisher: American Association for Cancer Research (AACR)
Date: 05-2015
DOI: 10.1158/1538-7445.SABCS14-OT3-1-03
Abstract: Background: The primary goals of treatment for patients (pts) with metastatic breast cancer (mBC) are maximising survival and preserving the quality of life. Intravenous (IV) trastuzumab has proven clinical benefits in pts with human epidermal growth factor receptor 2 (HER2)-positive mBC. Pertuzumab also targets HER2 through an independent epitope to that of trastuzumab. Addition of pertuzumab to the established combination of trastuzumab and docetaxel has shown improved efficacy with acceptable toxicity in mBC (Swain et al. Lancet Oncol 2013 :461-71) they are considered standard of care. Subcutaneous (SC) and IV trastuzumab formulations have shown comparable efficacy but SC administration is preferred by pts for reducing duration of clinic visits (Pivot, et al. Lancet Oncol 2013 : 962–970). The combination of IV pertuzumab and SC trastuzumab has not been studied. The aim is to assess safety, tolerability, and efficacy of combining IV pertuzumab with SC trastuzumab and a taxane, as first-line therapy in pts with HER2-positive mBC. Trial Design: SAPPHIRE is an open-label, multicentre, Phase IIIb study. Pts will receive IV pertuzumab every 3 weeks with a loading dose of 840 mg and subsequent doses at 420 mg combined with SC trastuzumab at 600 mg/5 mL every 3 weeks and a taxane (docetaxel, paclitaxel, or nab-paclitaxel regimen determined by the investigator). Treatment will continue until disease progression, unacceptable toxicity, or pts withdraw consent, whichever occurs first. The study is expected to run for 42 months. Eligibility: Pts aged ≥18 years old with histologically or cytologically confirmed HER2-positive [immunohistochemistry (IHC) positive at 3+ or in situ hybridisation-positive (ISH+)] mBC with at least one measurable lesion and/or non-measurable disease according RECIST version 1.1 and ECOG performance status (PS) 0-2 are eligible. Specific Aims: The primary objective is to assess the safety and tolerability of combining IV pertuzumab with SC trastuzumab and investigator’s choice taxane chemotherapy. The secondary objectives are to assess the efficacy of the first-line combination of pertuzumab, trastuzumab, and taxane chemotherapy and second-line treatments for mBC after disease progression. Statistical Methods: Primary safety analyses will report incidence and severity of adverse events (AEs)/serious AEs, AEs leading to premature discontinuation of study treatment and evidence of cardiac dysfunction. Secondary safety analyses will include exposure and duration of study treatment, ECOG PS and laboratory data. Secondary efficacy analyses will report the overall response rate, progression-free survival, event-free survival and overall survival. Continuous data will be summarised using mean, median, range, standard deviation, and standard error. Discrete data will be summarised using frequency counts and percentages. Time-to-event analyses will be based on Kaplan-Meier methodology. Accrual: The planned 50 pts will be recruited from 13 Australian Centres. The study started in December 2013 with 24 pts now enrolled. Clinicaltrials.gov#NCT02019277. Citation Format: Natasha Woodward, Richard H De Boer, Andrew Redfern, Vita Von Neumann-Cosel, Ronelle M Heath, Jane Beith. An open-label, multicentre, phase IIIb study with intravenous administration of pertuzumab, subcutaneous trastuzumab, and a taxane in patients with HER2-positive metastatic breast cancer (SAPPHIRE) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2015 (9 Suppl):Abstract nr OT3-1-03.
Publisher: Oxford University Press (OUP)
Date: 30-06-2015
Publisher: Wiley
Date: 10-01-2022
Publisher: Elsevier BV
Date: 06-2016
DOI: 10.1016/J.CRITREVONC.2016.03.014
Abstract: The platinum analogues, cisplatin and carboplatin, are among the most widely used chemotherapeutic agents in oncology. Both agents have a broad spectrum of clinical activity in numerous malignancies including gynaecological cancers, germ cell tumours, head and neck cancer, thoracic cancers and bladder cancer. Although the final mechanism of inducing tumour cell apoptosis is similar for both compounds, cisplatin has been shown to be more effective in treating specific tumour types. Whilst more favourable toxicity profiles are often associated with carboplatin, this can frequently translate to inferior response in certain malignancies. This review succinctly collates the evidence for the preferential use of these platinum analogues in particular settings in addition to the long-standing dilemma surrounding the paucity of biomarkers predicting response to these agents.
Publisher: Bioscientifica
Date: 26-09-2019
Publisher: Wiley
Date: 03-2016
DOI: 10.1111/AJCO.12491
Abstract: Endocrine therapy for the treatment of hormone receptor positive, HER2 negative, metastatic breast cancer is continually evolving. We systematically reviewed phase 2 and 3 randomized controlled trials (RCTs) of agents used in this setting to assess the effectiveness and safety of these agents for postmenopausal women. Across the 32 studies in more than 10,000 patients, the greatest improvement in progression-free survival (PFS) was seen with the addition of a cyclin-dependent kinase (CDK)4/6 inhibitor to standard endocrine therapy. Treatment with a mammalian target of rapamycin (mTOR) inhibitor, phosphoinositol-3-kinase (Pi3K) inhibitor, vascular endothelial growth factor (VEGF) inhibitor and with a selective estrogen receptor degrader (SERD) also showed benefit in PFS for selected trials. Overall survival (OS) improved with the use of mTOR inhibitors and a SERD however, studies were not powered for an OS endpoint. Encouraging results from early studies of histone deacetylase (HDAC) and B-cell lymphoma (BCL2) inhibitors are yet to be confirmed in phase III clinical trials. Study discontinuation rates and toxicity-related deaths were highest with VEGF inhibitors in combination with endocrine therapy, limiting their use in hormone receptor positive breast cancer. CDK4/6 inhibitors and mTOR inhibitors appeared to have activity in both first and second line settings, but required additional monitoring for common toxicities. The activity of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors was limited to the first-line setting and treatment discontinuation rates were higher than with mTOR inhibitors and SERDs. Overall, PFS benefit appears to be greatest when agents acting on CDK4/6, mTOR and Pi3K pathways, and SERDs are added to standard endocrine therapy. If these early results persist in further studies, these data are likely to change the way we treat hormone receptor positive, HER2 negative metastatic breast cancer. In the follow-up article to this review, we will consider the potential future treatment options for these patients.
Publisher: Wiley
Date: 10-2018
DOI: 10.1111/AJCO.13064
Abstract: Resistance to endocrine therapy is a significant therapeutic challenge in the treatment of women with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. Cyclin-dependent kinase (CDK)4/6 inhibitors in combination with endocrine therapy have been shown to improve progression free survival, overall response rate and clinical benefit rate in women with HR+ HER2- metastatic breast cancer compared with endocrine therapy alone. This review examines the clinical evidence to support the use of CDK4/6 inhibitors in first and second line settings. Practical guidance is provided for the use of CDK4/6 inhibitors, including tolerability data, monitoring requirements and management of key toxicities for each of the available agents.
Publisher: Wiley
Date: 03-2015
DOI: 10.1111/AJCO.12492
Abstract: Endocrine therapy is an established and effective treatment strategy for hormone receptor positive metastatic breast cancer. The clinical utility of endocrine therapy is lost over time due to evolving changes in tumor biology and the development of endocrine resistance. Many agents targeting the intracellular signaling pathways associated with endocrine resistance are in development. Encouraging early results have been seen for agents which directly target the estrogen receptor (ER), inhibitors of co-signaling pathways, inhibitors of ER chaperones, ER antagonists able to inhibit mutated or otherwise activated ERs, and modulators of histone acetylation restoring synthesis of ER signaling components. Following our systematic review of treatments with established benefits in this supplement, we review some of the more promising new strategies for overcoming endocrine resistance, looking at the impact on disease control and quality of life for women with hormone receptor positive, HER2 negative breast cancer. We also examine the biomarkers that may guide selection of the best therapy for the in idual.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2018
Publisher: MDPI AG
Date: 05-01-2023
DOI: 10.3390/CURRONCOL30010054
Abstract: This study aimed to investigate nutritional status, body composition, dietary protein intake, handgrip strength, 6 min or 4 m walk tests, self-reported physical activity, physical function, and quality of life (QoL-EORTC-QLQc30) at commencement of chemotherapy to detect changes over time (from commencement of chemotherapy, and after 3, 6, 12, 26 and 52 weeks) in women with metastatic breast cancer (MBC) and to investigate the relationship between nutritional variables. ‘Sarcopenia’ was defined as low muscle mass and strength, ‘myosteatosis’ as muscle fat-infiltration (CT scan). Continuous variables were analysed using paired t-tests between baseline and follow-ups. Fifteen women (54y, 95% CI [46.3 .2]) were recruited. At baseline, malnutrition was present in 3 (20%) participants, sarcopenia in 3 (20%) and myosteatosis in 7 (54%). Thirteen (87%) participants had low protein intake low handgrip strength was observed in 0, and low walk test distance and physical activity in four (27%) participants. Physical function and QoL were low in 10 (67%) and 9 (60%), respectively. QoL between baseline and 52 weeks decreased by 11.7 (95% CI [2.4 .9], p = 0.025). Other variables did not significantly change over time. In this small study s le, myosteatosis, low dietary protein intake, low exercise levels and impaired quality of life and physical function are common.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 06-2022
DOI: 10.1200/JCO.2022.40.16_SUPPL.602
Abstract: 602 Background: We examined the efficacy and safety of neoadjuvant ipilimumab and nivolumab combined with paclitaxel following suboptimal response to anthracycline-based chemotherapy in patients with early-stage TNBC. Methods: This single arm multicentre phase 2 study enrolled 34 patients in 8 sites. Patients were aged ≥18 years with previously untreated stage 3 TNBC and were required to have ≥15mm of tumor remaining or 10mm of tumor with one positive lymph node after 4 cycles of anthracycline-based therapy. A suboptimal response subset at baseline was defined as 50% reduction in tumor volume after initial anthracycline-based chemotherapy. Patients received neoadjuvant ipilimumab 1mg/kg IV 6 weekly for 2 doses and nivolumab 240mg every 2 weeks for 6 doses, with weekly paclitaxel at 80mg/m 2 for 12 weeks, followed by surgery. Nivolumab (480mg 4-weekly) continued post operatively for further 9 months. Primary endpoint was pathological complete response (pCR) in breast and axilla, with secondary endpoints pCR in the suboptimal responders, pCR in PD-L1 positive patients (≥1% by SP142 assay), clinical response in the breast (ORR by RECIST), event-free (EFS) and overall survival (OS). Results: Between December 2018 and April 2020, 34 patients were enrolled, 33 were evaluable for the primary endpoint. Median age was 46.6yrs. At diagnosis, all patients were clinical stage III (AJCC v8), 16/34 (47%) were node positive, 8/31 (26%) were PD-L1 positive. At study entry (following anthracycline-based chemo), the median tumor size by ultrasound was 28mm (12-62). 16/33 (48%) were considered suboptimal responders. The pCR rate (ypT0ypN0) was 24.2% (95% CI, 11.09-42.26) in all evaluable, 37.5% [3/11] in PD-L1+ and 23% [5/22] in PD-L1- patients. In patients with suboptimal anthracycline response ( 50% tumor reduction), the pCR rate was 18.8% (95% CI, 8.52-75.51) (3/16). ORR in the breast was 57.6% (19/33) in all evaluable patients and 43.7% (8/20) in the suboptimal responders. The number of patients with residual cancer burden (RCB) class 0,1,2,3 was 8 (24%), 1 (3%), 19 (57.5%) and 5 (15%) respectively. With 14 months median follow up, 12-months EFS was estimated at 85% and OS 94%. For patients with pCR vs non-pCR, the hazard ratio (HR) for EFS was 0.62, 12 mo EFS was 100% vs 75%. In the neoadjuvant phase, 15/33 (45%) patients experienced at least one grade 3-4 adverse event. Most common immune-related event was grade 1 or 2 pneumonitis 9/33 (27%), which generally occurred with fever after the first dose of ipilimumab, and resolved. There was one case of grade 3 colitis. Conclusions: In these high risk patients, the addition of ipilimumab and nivolumab to neoadjuvant paclitaxel resulted in promising ORR and pCR rates, regardless of PD-L1 status. Rates of low grade pneumonitis were high. Follow up continues. Clinical trial information: ACTRN12617000651381.
Publisher: Wiley
Date: 10-2018
DOI: 10.1111/AJCO.13065
Abstract: Cyclin-dependent kinase (CDK4/6) inhibitors in combination with endocrine therapy are currently the optimal first line treatment for hormone receptor (HR) positive, human epidermal growth factor receptor 2 (HER2) non- lified metastatic breast cancer (MBC). However, not all patients benefit from this treatment and all patients will inevitably progress. Identifying therapeutic strategies in this setting is therefore of immediate clinical importance. We present an overview of the mechanisms of resistance to CDK4/6 inhibitors and review potential biomarkers that may guide therapy selection. We also discuss the use of CDK4/6 inhibitors in the context of non-HR-positive/HER2-non- lified breast cancer and in combination with therapies other than endocrine therapy.
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2019
DOI: 10.1200/JCO.2019.37.15_SUPPL.1071
Abstract: 1071 Background: The PARP inhibitor TALA was approved in the US for treatment of g BRCA-mutated ABC based in part on the EMBRACA study. Understanding the outcomes of EMBRACA pts relative to prior CT is a current unmet need. Methods: EMBRACA was a randomized Phase 3 trial comparing TALA 1 mg daily vs PCT (capecitabine, eribulin, gemcitabine, vinorelbine) in g BRCA-mutated ABC. Clinical outcomes were assessed by line of prior CT for ABC in intent-to-treat (ITT), triple-negative breast cancer (TNBC), and hormone receptor-positive (HR+) breast cancer cohorts. Results: 431 pts were randomized (ITT TALA 287 PCT: 144). TALA was generally more effective than PCT across efficacy endpoints regardless of line of CT (Table). For the ITT population, TALA improved progression-free survival (PFS) and objective response rate (ORR) vs PCT for each line of CT assessed. Other prespecified subgroups (TNBC and HR+) will be presented. Conclusions: In pts with g BRCA-mutated ABC, TALA demonstrated improvements in clinical outcomes compared with PCT regardless of prior lines of CT. Clinical trial information: NCT01945775. [Table: see text]
Publisher: eLife Sciences Publications, Ltd
Date: 09-03-2021
DOI: 10.7554/ELIFE.60060
Abstract: From 1985 to 2016, the prevalence of underweight decreased, and that of obesity and severe obesity increased, in most regions, with significant variation in the magnitude of these changes across regions. We investigated how much change in mean body mass index (BMI) explains changes in the prevalence of underweight, obesity, and severe obesity in different regions using data from 2896 population-based studies with 187 million participants. Changes in the prevalence of underweight and total obesity, and to a lesser extent severe obesity, are largely driven by shifts in the distribution of BMI, with smaller contributions from changes in the shape of the distribution. In East and Southeast Asia and sub-Saharan Africa, the underweight tail of the BMI distribution was left behind as the distribution shifted. There is a need for policies that address all forms of malnutrition by making healthy foods accessible and affordable, while restricting unhealthy foods through fiscal and regulatory restrictions.
Publisher: Elsevier BV
Date: 09-2021
Publisher: Wiley
Date: 05-11-2018
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2017
DOI: 10.1158/1538-7445.SABCS16-OT2-01-13
Abstract: Background: Cancer cells with deleterious mutations in breast cancer susceptibility genes 1 and 2 (BRCA1/2) are deficient in the DNA double-strand break repair mechanism, rendering them highly dependent on the single-strand break repair pathway, regulated by poly(ADP-ribose) polymerase (PARP). Inhibition of PARP results in synthetic lethality in cells with a BRCA1/2 mutation because of accumulation of irreparable DNA damage PARP inhibitors have the potential to be selectively toxic for BRCA-mutated cells. In addition to catalytic inhibition, it has been shown that some PARP inhibitors induce PARP trapping at sites of DNA damage. The capacity to trap PARP-DNA complexes varies widely across different PARP inhibitors and is not correlated with PARP catalytic inhibition. Preclinical models have shown trapping PARP on DNA is more potent at inducing cancer cell death than enzymatic inhibition of PARP alone. Talazoparib is a dual-mechanism PARP inhibitor that both inhibits the PARP enzyme and effectively traps PARP on DNA, preventing DNA damage repair and resulting in cell death in BRCA1/2-mutated cells. In preclinical studies, talazoparib at nanomolar concentrations showed the highest efficiency at trapping PARP-DNA complexes relative to other PARP inhibitors. In a previous phase 1/2 clinical study, talazoparib as monotherapy (1 mg once daily) resulted in a 50% response rate and an 86% clinical benefit rate at 24 weeks in 14 patients with a germline BRCA1/2 mutation and advanced breast cancer (aBC). Methods: This open-label, randomized, 2-arm, international phase 3 trial (EMBRACA) compares the efficacy and safety of talazoparib with protocol-specific physician's choice (capecitabine, eribulin, gemcitabine or vinorelbine) in patients with aBC. The primary objective is progression-free survival by central imaging. Secondary objectives are objective response rate, overall survival, safety and pharmacokinetics of talazoparib. Exploratory objectives include health-related quality of life measurements and biomarker research in blood and tumor s les that may permit characterization of mechanisms involved in tumor sensitivity and resistance to talazoparib. Key patient eligibility criteria include aged ≥18 years with histologically/cytologically confirmed breast cancer locally advanced and/or metastatic disease appropriate for systemic single-agent cytotoxic chemotherapy deleterious or pathogenic germline BRCA1/2 mutations by central laboratory ≤3 prior cytotoxic chemotherapy regimens for advanced disease (prior platinum is allowed provided patients did not relapse within 6 months in the adjuvant setting or did not progress on platinum therapy) prior treatment with a taxane and/or anthracycline unless medically contraindicated and ECOG performance status ≤2. Patients (N=429) will be randomized 2:1 to receive either talazoparib capsules (1 mg/day, 21-day cycles) or physician's choice treatment. This trial is currently enrolling patients from the USA, Europe, Israel, Ukraine, Russia, Korea, Australia, Taiwan and Brazil (NCT01945775). This study is funded by Me ation, Inc. Citation Format: Litton J, Ettl J, Hurvitz SA, Mina LA, Rugo HS, Lee K-H, Yerushalmi R, Woodward N, Goncalves A, Moreno F, Roche H, Im Y-H, Martin M, Bhattacharya S, Peterson A, Hannah A, Eiermann W, Blum J. A phase 3, open-label, randomized, 2-arm international study of the oral dual PARP inhibitor talazoparib in germline BRCA mutation subjects with locally advanced and/or metastatic breast cancer (EMBRACA) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium 2016 Dec 6-10 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2017 (4 Suppl):Abstract nr OT2-01-13.
Publisher: Elsevier BV
Date: 04-2018
Publisher: Elsevier BV
Date: 11-2020
Publisher: Elsevier BV
Date: 06-2019
DOI: 10.1016/J.CLBC.2019.02.008
Abstract: The primary objective of this study was to assess the safety and tolerability of combination pertuzumab, subcutaneous trastuzumab (Herceptin), and investigator's choice of taxane chemotherapy in previously untreated patients with human epidermal growth factor receptor 2-positive metastatic breast cancer. Efficacy was a secondary objective. This study was an open-label, non-randomized study of patients with human epidermal growth factor receptor 2-positive metastatic breast cancer who had no previous systemic non-hormonal anti-cancer therapy for metastatic disease. The primary endpoints included adverse events (AE), serious AEs, and cardiac AEs. Secondary endpoints included overall response rate, progression-free survival, and overall survival. Patients were treated with pertuzumab and subcutaneous trastuzumab in 3-weekly cycles with taxane chemotherapy until disease progression, unacceptable toxicity, or withdrawal of consent and followed for a minimum of 24 months from initiation of study treatment. Fifty patients were enrolled and included in the analysis. All patients experienced at least 1 AE, with diarrhea, fatigue, peripheral neuropathy, alopecia, rash, and nausea the most common. Three patients experienced at least 1 grade 3 event of suspected cardiac origin (cardiac failure, cardiomyopathy, hypertension). Six patients withdrew from therapy owing to AEs (cardiac failure, drug hypersensitivity, decreased left ventricular ejection fraction, syncope, and bullous dermatitis). Taxane chemotherapy comprised nab-paclitaxel (74.0% of patients), docetaxel (28.0%), or paclitaxel (4.0%). The overall response rate was 73.3% (95% confidence interval, 58.1%-85.4%), the median progression-free survival was 17.0 months (95% confidence interval, 12.5-31.2 months), and the median overall survival was not reached. Subcutaneous trastuzumab in this combination has an acceptable safety and tolerability profile, including cardiac safety profile. Safety and efficacy appear similar to previous studies of intravenous trastuzumab in this combination.
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2018
DOI: 10.1158/1538-7445.SABCS17-P3-14-06
Abstract: Background: Chemotherapy induced peripheral neuropathy (CIPN) remains a common treatment related adverse event for breast cancer (BC) patients. CIPN interferes with the ability to complete chemotherapy & therefore potentially compromises survival outcomes. CIPN can worsen health-related quality of life and also add to the ongoing morbidity experienced by BC survivors. Previously, systematic reviews & ASCO guidelines have examined CIPN across many cancer types & different chemotherapies, which may lead to the introduction of confounding factors not relevant to BC patients. A recent prospective cohort also identified other specific lifestyle factors associated with CIPN in BC patients (1). From our search, a systematic review specifically looking at CIPN in BC patients has not previously been undertaken. Methods: We conducted a systematic search in PubMed, EMBASE, CINAHL and CENTRAL. Clinical trials and observational studies for all potential pharmacological and non-pharmacological interventions were included. Risk of bias for full-text papers was assessed using the Cochrane Risk of Bias Assessment or the modified Newcastle Ottawa score. Results: Of 706 records being identified, 601 unique citations were screened with 21 full text papers retrieved for assessment, and 16 studies included in the qualitative assessment. We identified 10 randomised controlled trials (RCTs), one observational cohort study, and five controlled before-and-after studies (CBA). Pharmacological interventions which were investigated included calcium/magnesium infusion, glutamine, amifostine, goshajinkigan, omega 3 fatty acids, acetyl-L-carnitine, pregabalin, alpha-lipoic acid and minocycline. Non-pharmacological interventions included body mass index & lifestyle factors, electroacupuncture, exercise, limb hypothermia, carbon dioxide limb bathing and limb compression therapy. All trials identified were investigating primary prevention of CIPN in the setting of taxane chemotherapy. Improvements in the incidence of CIPN were reported with omega 3 fatty acids, glutamine and alpha-lipoic acid, but only one of these studies is a published RCT. In two of the studies, the benefit was identified only on physical examination, but no significant benefit with nerve conduction (NCS) testing. On subgroup analysis of trials investigating exercise, there was a benefit in the use of high intensity exercise versus low intensity exercise, particularly in patients & years old within a healthy weight range. Mixed results were seen with goshajinkigan. An increase in CIPN was seen with antioxidant use, electroacupuncture and acetyl L carnitine. Majority of the RCTs were associated with a high overall risk of bias. Conclusions: There has been a paucity of research on CIPN in BC patients. There were no interventions identified in this systematic review which show a clear clinical benefit in the prevention of CIPN in BC patients. BC patients may have specific lifestyle and hormonal factors which influence CIPN and this should prompt ongoing specific patient focussed research within this subgroup with large, blinded, randomised controlled trials. Greenlee, et al. Natl Cancer Inst 2017 109(2). Citation Format: Roberts KE, Feng S, Adsett I, Rickett K, Woodward N. The prevention and management of chemotherapy-induced peripheral neuropathy in breast cancer patients: A systematic review [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium 2017 Dec 5-9 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2018 (4 Suppl):Abstract nr P3-14-06.
Publisher: Springer Science and Business Media LLC
Date: 05-2019
Publisher: Wiley
Date: 29-01-2020
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2017
DOI: 10.1158/1538-7445.SABCS16-P4-21-31
Abstract: Background: Pertuzumab targets the human epidermal growth factor receptor 2 (HER2) through an independent epitope to that of trastuzumab. Improved efficacy with acceptable toxicity has been shown, in metastatic breast cancer (mBC) for pertuzumab in combination with intravenous (IV) trastuzumab and docetaxel.1 This study aimed to assess the safety, tolerability and efficacy of combining IV pertuzumab with subcutaneous (SC) trastuzumab and a taxane, as 1st-line therapy in patients (pts) with HER2+ mBC. We present safety data with 19 months (mo) of median follow-up. Methods: SAPPHIRE (NCT02019277) is a multicentre, open-label, phase IIIb study. Primary objective: safety and tolerability of IV pertuzumab + SC trastuzumab and investigator's choice of taxane. Pts ≥18 years with confirmed HER2+ mBC and ECOG PS 0-2 were included. The incidence and severity of adverse events (AEs), serious (S) AEs and AEs leading to premature discontinuation of study treatment were analyzed by taxane group. Results: 50 pts enrolled in the study. Taxanes of choice: nab-paclitaxel (NP n=36), docetaxel (D n=13) and paclitaxel (P n=1). As of March 4th 2016, 34 pts had withdrawn from study median follow-up= 19mo (range: 6-27). 28(56%) pts received & cycles of study medication. All patients experienced AEs with 326 AEs in the D group and 675 in the NP group the majority being grade 1-2. The most common AEs were diarrhea, fatigue, peripheral neuropathy, alopecia, and rash. Grade 3+ AEs (n=77) were reported in 30 (60%) pts, 20 in the D group (8 pts 62%) and 57 in the NP group (22 pts, 61%). The most common grade 3+ AEs in the D group were febrile neutropenia (4 pts, 31%) and neutropenia (3 pts 23%) and in the NP group neutropenia (3 pts 8%), anemia, diarrhea, cellulitis, peripheral neuropathy, LVEF decreased and pulmonary embolism each reported in 2(6%) pts . SAEs (n=44) were reported in 25(50%) pts, 11 (8 pts 62%) in the D group and 33 (17 pts 47%) in the NP group. The most common SAEs in the D group were febrile neutropenia (4 pts, 31%) and pyrexia (2 pts, 15%) and in the NP group: pyrexia (5 pts, 14%), cellulitis (2 pts, 6%) and pulmonary embolism (2 pts, 6%). AEs of suspected cardiac disorders (n=12) were reported in 7(14%) pts atrial fibrillation, cardiomyopathy, myocardial ischemia, and dyspnea each reported in 1(2%) pt and LVEF decreased, palpitation, hypertension each reported in 2(4%) pts. AEs leading to study drug discontinuation (n=6) were reported in 6(12%) pts [LVEF decreased (3), drug hypersensitivity, syncope and blister]. AEs leading to chemotherapy discontinuation (n=24) were reported in 10(20%) pts. 4(8%) pts died on study (disease progression). Conclusion: No new safety signals have been reported in this study. Of further clinical interest is the finding that no cases of febrile neutropenia were reported in the NP taxane group compared to 4 in the D group. The safety profile remains consistent with the CLEOPATRA,1 PERUSE2 and HannaH3 studies, indicating the combination is safe and tolerable. 1.Baselga, et al. NEJM 2012 :109 2.Bachelot, et al. JCO 2014 :5s(abstr#548) 3.Ismael, et al. Lancet Onc 2012 :869. Citation Format: Woodward N, De Boer RH, Redfern A, White M, Roberts W, Truman M, Beith J. Updated safety results from the first multicenter, open-label, phase IIIb study investigating the combination of pertuzumab with subcutaneous trastuzumab and a taxane in patients with HER2-positive metastatic breast cancer (SAPPHIRE) [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium 2016 Dec 6-10 San Antonio, TX. Philadelphia (PA): AACR Cancer Res 2017 (4 Suppl):Abstract nr P4-21-31.
Publisher: Elsevier BV
Date: 03-2017
DOI: 10.1016/J.CRITREVONC.2017.01.010
Abstract: Aromatase Inhibitors (AI) are widely used for the adjuvant treatment of hormone receptor positive breast cancers in the post-menopausal population. AI are often associated with significant joint and muscular symptoms symptoms that are commonly referred to as aromatase inhibitor-associated musculoskeletal syndrome (AIMSS). AIMSS adversely impacts health-related quality of life of many patients, and reduces AI compliance. Although there are informal practice recommendations, the limited current level of evidence for management of AIMSS for breast cancer patients on aromatase inhibitors has made development of formal guidelines challenging, and remains an unmet need. This is the first systematic review to consider the evidence for all pharmacological and non-pharmacological interventions in the treatment of AIMSS, including physical therapy, acupuncture and complementary therapies.
No related grants have been discovered for Natasha Elizabeth Woodward.