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PURPOSE: Tumor angiogenesis controlled predominantly by vascular endothelial growth factor and its receptor (VEGF-VEGFR) interaction plays a key role in the growth and propagation of cancer cells. However, the newly formed network of blood vessels is disorganized and leaky. Pre-treatment with anti-angiogenic agents can "normalize" the tumor vasculature allowing effective intra-tumoral delivery of standard chemotherapy. Immunohistochemistry (IHC) analysis was applied to investigate and compare the vascular normalization and anti-angiogenic effects of two commonly used anti-angiogenic agents, Sunitinib and Bevacizumab, administered prior to chemotherapy in HER2-negative breast cancer patients. METHODS: This prospective clinical trial enrolled 38 patients into a sunitinib cohort and 24 into a bevacizumab cohort. All received 4 cycles of doxorubicin/cyclophosphamide chemotherapy and pre-treatment with either sunitinib or bevacizumab. Tumor biopsies were obtained at baseline, after cycle 1 (C1) and cycle 4 (C4) of chemotherapy. IHC was performed to assess the tumor vascular normalization index (VNI), lymphatic vessel density (LVD), Ki67 proliferation index and expression of tumor VEGFR2. RESULTS: In comparison to Bevacizumab, Sunitinib led to a significant increase in VNI post-C1 and C4 (p < 0.001 and 0.001) along with decrease in LVD post-C1 (p = 0.017). Both drugs when combined with chemotherapy resulted in significant decline in tumor proliferation after C1 and C4 (baseline vs post-C4 Ki67 index p = 0.006 for Sunitinib vs p = 0.021 for Bevacizumab). Bevacizumab resulted in a significant decrease in VEGFR2 expression post-C1 (p = 0.004). CONCLUSION: Sunitinib, in comparison to Bevacizumab showed a greater effect on tumor vessel modulation and lymphangiogenesis suggesting that its administration prior to chemotherapy might result in improved drug delivery. TRIAL REGISTRY: ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).
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Neoplasias de la Mama , Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Humanos , Inmunohistoquímica , Sunitinib/uso terapéutico , Factor A de Crecimiento Endotelial VascularRESUMEN
PURPOSE: To identify a structure to explain the relationship between socio-clinico factors, necessity-concerns beliefs, and perceived barriers to adherence with adjuvant endocrine therapy (AET) amongst women with breast cancer. METHODS: Participants were 244 patients with early-stage breast cancer recruited from two tertiary hospitals from May 2015 to December 2018 who completed questionnaires on medication adherence (Simplified Medication Adherence Questionnaire), necessity-concerns beliefs (Beliefs about Medicine Questionnaire), and barriers to adherence (Adherence Starts with Knowledge Questionnaire). Socio-clinico variables were collected via interview and medical records review. Structural equation modelling was applied to examine the relationships between these variables and possible mediating effects of necessity-concerns beliefs on adherence to AET. RESULTS: The median age of the study participants was 61 (range 32-80) years and the median duration on AET was 1.6 (IQR 1.2-2.6) years. Adherence was positively associated with age (ß = 0.145, 95% CI: 0.011 to 0.279, p = 0.034) and negatively associated with barriers (ß = - 0.381, 95% CI: - 0.511 to - 0.251, p < 0.001). There was no effect of Necessity (ß = 0.006, 95% CI: - 0.145 to 0.158, p = 0.933) or Concerns (ß = 0.041, 95% CI: - 0.117 to 0.199, p = 0.614) on adherence. Necessity-concerns beliefs were also not significant mediators in the relationship between socio-clinico factors and medication adherence. CONCLUSIONS: Older age and lower barriers to adherence were associated with higher adherence scores. Necessity-concerns beliefs did not have a significant effect on adherence as majority of the patients identified forgetfulness as a reason for non-adherence.
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Antineoplásicos Hormonales , Neoplasias de la Mama , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/epidemiología , Terapia Combinada , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Análisis de Clases Latentes , Cumplimiento de la Medicación , Persona de Mediana Edad , Encuestas y CuestionariosRESUMEN
BACKGROUND: Family caregivers of cancer patients often experience an impaired quality of life (QOL) and emotional distress as a result of their caregiving duties, which may potentially influence the quality of care of their care recipients. The COPE (Caregivers of cancer Outpatients' Psycho-Education support group therapy) intervention was developed as a response to the lack of work done among family caregivers of ambulatory cancer patients in Asia. This group intervention comprised four weekly sessions simultaneously targeting psychoeducation, skills training, and supportive therapy. The present study sought to evaluate the pilot COPE intervention using both quantitative and qualitative measures. The Hospital Anxiety and Depression Scale (HADS) was used to measure both depression and anxiety, while the Caregiver QOL - Cancer (CQOLC) measured caregiver QOL. These instruments were measured at baseline pre-intervention, and immediately post-intervention. A waitlist control group design was adopted. A subset of caregivers from the intervention group were invited for a semi-structured interview post-intervention. FINDINGS: Quantitative analyses suggest that while QOL remained stable in control group participants, intervention group participants experienced QOL improvements - both in overall QOL and in the specific domain of burden. There were no significant differences in the trajectories of depression and anxiety in both groups. Qualitative analyses suggest that this might have been a result of the intervention not only equipping participants with the relevant coping skills, but also providing a platform for emotional expression and situational reappraisal. CONCLUSIONS: The COPE intervention has shown some efficacy in helping family caregivers of cancer patients, but more work is required before this can be implemented. TRIAL REGISTRATION: Current Controlled Trials NCT02120183 . Registered 17 April 2014. Retrospectively registered.
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Adaptación Psicológica , Ansiedad/prevención & control , Cuidadores/educación , Cuidadores/psicología , Depresión/prevención & control , Grupos de Autoayuda , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/terapia , Proyectos Piloto , Calidad de VidaRESUMEN
PURPOSE: Cancer patients experience distress and high levels of psychosocial concerns. However, in Asian countries like Singapore, patients are often unwilling to seek support and help from mental healthcare professionals, but, instead, are more willing to confide in nurses. This quasi-experimental study developed and tested the efficacy of a brief nurse-led psychosocial intervention to alleviate these patients' distress, minor psychiatric morbidity, and psychosocial concerns. METHODS: The semi-structured intervention comprised 20- to 30-minute face-to-face sessions with trained oncology nurses, monthly for 2 months and then bimonthly for 4 months. Patients received psycho-education on symptoms of stress, anxiety, and depression and counseling and were taught behavioral techniques such as deep breathing, progressive muscle relaxation, and positive self-talk. RESULTS: The results of this study found that patients who received the intervention had reduced distress, depression, and anxiety levels and improved quality of life (QOL) at 6 months. CONCLUSIONS: Although further research is necessary to explore the efficacy and viability of this intervention, findings support brief nurse-led psycho-educational interventions in Asian settings especially for cancer patients reluctant to seek help from mental health professionals.
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Ansiedad/enfermería , Depresión/enfermería , Neoplasias/enfermería , Neoplasias/psicología , Ansiedad/etiología , Ansiedad/psicología , Pueblo Asiatico , Consejo/métodos , Depresión/etiología , Depresión/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Rol de la Enfermera , Proyectos Piloto , Calidad de Vida , SingapurRESUMEN
PURPOSE: The Caregiver Quality of Life Index-Cancer (CQOLC) is used worldwide to determine levels of quality of life of caregivers of patients with cancer; however, the few studies examining the underlying factor structure of the CQOLC have revealed differences between Western and Eastern cultures. This study sought to confirm the differences in the factor structures between the original CQOLC and a Taiwanese (Mandarin) version. METHODS: A total of 183 caregivers from a cancer center in Singapore participated in this exploratory cross-sectional study. All participants completed the CQOLC and a sociodemographic form; 30 participants repeated the CQOLC two weeks later. RESULTS: Test-retest reliability was adequate for the CQOLC; however, confirmatory factor analyses did not support either the original four-factor model or the Taiwanese five-factor model. Exploratory factor analyses suggested the retaining of five factors to form a 25-item Singapore version (CQOLC-S25): burden, physical/practical concerns, emotional reactivity, self-needs, and social support. Inter-factor and factor scale correlations were positively significant for all factors except Support, which was negatively correlated with emotional reactivity and self-needs. CONCLUSIONS: Cross-cultural differences, which require further investigations, appear to underlie the utility and understanding of the CQOLC. More research is needed to better understand the needs of Singapore caregivers.
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Atención Ambulatoria , Cuidadores/psicología , Calidad de Vida , Encuestas y Cuestionarios , Adulto , Estudios Transversales , Características Culturales , Análisis Factorial , Femenino , Necesidades y Demandas de Servicios de Salud , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/terapia , Reproducibilidad de los Resultados , Singapur , Apoyo Social , Factores Socioeconómicos , Adulto JovenRESUMEN
PURPOSE: Psychosocial distress in oncology patients may significantly interfere with their health outcomes and quality of life. Nurses work closely with their patients and are in the best position to screen for distress and provide timely intervention. It is thus important for nurses working in oncology settings to be equipped and prepared to address distressing psychosocial issues. The present study aims to investigate the impact of a training program in psychosocial care on nurses' knowledge, attitudes, and clinical practice behaviors. METHODS: A total of 180 nurses working in medical oncology and radiation oncology departments at the National University Cancer Institute Singapore underwent a training program in psychosocial care as part of their continuing nursing education curriculum. One hundred fifty four of these nurses completed a self-designed questionnaire on nurses' knowledge, attitudes, and practice behaviors (KAPb) at all four time points: baseline, post-training, and at 6 and 12 weeks post-training, respectively. RESULTS: The self-designed KAPb questionnaire proved adequate for this study. Positive gains on applied knowledge and practice behaviors were sustained over a 12-week period. There were no changes in theoretical knowledge. A decreasing trend in attitudes was noted, although this was specific to the participants' attitudes toward the importance of emotional concerns as compared to physical concerns in cancer treatment. Enrolled nurses seemed to have higher starting levels of theoretical knowledge than their registered counterparts were. There were no other differences on demographic variables in relation to the efficacy of the training program. CONCLUSIONS: The training program was successful in improving the applied knowledge and practice behaviors of nurses in providing psychosocial care for cancer patients. However, further refinement to the program, with particular attention to nurses' existing training and years of clinical nursing experience, would enhance staff empowerment and care improvement.
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Educación Continua en Enfermería/métodos , Conocimientos, Actitudes y Práctica en Salud , Neoplasias/enfermería , Neoplasias/psicología , Enfermeras y Enfermeros/psicología , Enfermería Oncológica/educación , Actitud del Personal de Salud , Femenino , Humanos , Masculino , Singapur , Encuestas y CuestionariosRESUMEN
INTRODUCTION: Research has shown that single-item tools, like the Distress Thermometer (DT), are comparable to longer ones, like the Hospital Anxiety and Depression Scale (HADS). In this study, we tested the validity of the DT in a population of Singapore cancer outpatients, and determined the cut-off scores on the DT for clinically relevant distress and an impaired quality of life (QOL). We also documented the prevalence of anxiety, depression, and QOL impairments in this population. METHODS: One hundred and five patients (Mdn age=51-60years, 64% female, and 71% Chinese) diagnosed with various cancers participated in this study. They completed a standard socio-demographic form, the DT and the Problem List, the HADS, and the EuroQOL Quality of Life Scale (EQ-5D). RESULTS: Almost a third of patients had clinically significant emotional distress, with 15%-16% having probable levels of anxiety and depression. Almost half (41%-55%) had an impaired QOL compared to Singapore population norms. Receiver operating characteristic curve analyses identified an area under the curve of 0.89 (SE=0.36, 95% CI [0.82, 0.96], p<.001) when compared to the HADS cut-off score of 15. A cut-off score of 5 on the DT had the best sensitivity (0.88) and specificity (0.81). Participants above the DT cut-off score of 5 reported significantly more emotional problems (worry, nervousness, depression, sadness), insurance/finance-related problems, and sleep problems. They also scored significantly lower on EQ-5D, with more QOL impairments in the domains of carrying out their usual activities and anxiety/depression. CONCLUSION: Levels of distress, anxiety, depression, and QOL impairments are high in this population. The DT was found to be a valid tool for distress screening in the Singapore cancer population, with a recommended cut-off score of 5.
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Neoplasias/complicaciones , Neoplasias/psicología , Pacientes Ambulatorios/psicología , Escalas de Valoración Psiquiátrica , Calidad de Vida/psicología , Estrés Psicológico/diagnóstico , Síntomas Afectivos/epidemiología , Ansiedad/diagnóstico , Ansiedad/epidemiología , Depresión/diagnóstico , Depresión/epidemiología , Depresión/psicología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psicometría , Singapur/epidemiología , Estrés Psicológico/complicaciones , Estrés Psicológico/epidemiologíaRESUMEN
OBJECTIVE: Ovarian clear cell carcinoma (OCCC) is associated with chemoresistance. Limited data exists regarding the efficacy of targeted therapies such as immune checkpoint inhibitors (ICI) and bevacizumab, and the role of secondary cytoreductive surgery (SCS). METHODS: We retrospectively analyzed genomic features and treatment outcomes of 172 OCCC patients treated at our institution from January 2000 to May 2022. Next-generation sequencing (NGS) was performed where sufficient archival tissue was available. RESULTS: 64.0% of patients were diagnosed at an early stage, and 36.0% at an advanced stage. Patients with advanced/relapsed OCCC who received platinum-based chemotherapy plus bevacizumab followed by maintenance bevacizumab had a median first-line progression-free survival (PFS) of 12.2 months, compared with 9.3 months for chemotherapy alone (hazard ratio=0.69; 95% confidence interval [CI]=0.33, 1.45). In 27 patients who received an ICI, the overall response rate was 18.5% and median duration of response was 7.4 months (95% CI=6.5, 8.3). In 17 carefully selected patients with fewer than 3 sites of relapse, median PFS was 35 months (95% CI=0, 73.5) and median overall survival was 96.8 months (95% CI=44.6, 149.0) after SCS. NGS on 58 tumors revealed common mutations in ARID1A (48.3%), PIK3CA (46.6%), and KRAS (20.7%). Pathogenic alterations in PIK3CA, FGFR2, and NBN were associated with worse survival outcomes. Median tumor mutational burden was 3.78 (range, 0-16). All 26 patients with available loss of heterozygosity (LOH) scores had LOH <16%. CONCLUSION: Our study demonstrates encouraging outcomes with bevacizumab and ICI, and SCS in select relapsed OCCC patients. Prospective trials are warranted.
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Introduction: Molecular profiling of metastatic breast cancer (MBC) through the widespread use of next-generation sequencing (NGS) has highlighted actionable mutations and driven trials of targeted therapy matched to tumour molecular profiles, with improved outcomes reported using such an approach. Here, we review NGS results and treatment outcomes for a cohort of Asian MBC patients in the phase I unit of a tertiary centre. Methods: Patients with MBC referred to a phase I unit underwent NGS via Ion AmpliSeq Cancer Hotspot v2 (ACH v2, 2014-2017) prior to institutional change to FoundationOne CDx (FM1; 2017-2022). Patients were counselled on findings and enrolled on matched therapeutic trials, where available. Outcomes for all subsequent treatment events were recorded to data cut-off on January 31, 2022. Results: A total of 215 patients were enrolled with successful NGS in 158 patients. The PI3K/AKT/PTEN pathway was the most altered with one or more of the pathway member genes PIK3/AKT/PTEN affected in 62% (98/158) patients and 43% of tumours harbouring a PIK3CA alteration. Tumour mutational burden (TMB) was reported in 96/109 FM1 sequenced patients, with a mean TMB of 5.04 mt/Mb and 13% (12/96) with TMB ≥ 10 mt/Mb. Treatment outcomes were evaluable in 105/158 patients, with a pooled total of 216 treatment events recorded. Matched treatment was administered in 47/216 (22%) events and associated with prolonged median progression-free survival (PFS) of 21.0 weeks [95% confidence interval (CI) 11.7, 26.0 weeks] versus 12.1 weeks (95% CI 10.0, 15.4 weeks) in unmatched, with hazard ratio (HR) for progression or death of 0.63 (95% CI 0.41, 0.97; p = 0.034). In the subgroup of PIK3/AKT/PTEN-altered MBC, the HR for progression or death was 0.57 (95% CI 0.35, 0.92; p = 0.02), favouring matched treatment. Per-patient overall survival (OS) analysis (n = 105) showed improved survival for patients receiving matched treatment versus unmatched, with median OS (mOS) of 30.1 versus 11.8 months, HR = 0.45 (95% CI 0.24, 0.84; p = 0.013). Objective response rate (ORR) in the overall population was similar in matched and unmatched treatment events (23.7% versus 17.2%, odds ratio of response 1.14 95% CI 0.50, 2.62; p = 0.75). Conclusions: Broad-panel NGS in MBC is feasible, allowing therapeutic matching, which was associated with improvements in PFS and OS.
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The Beliefs about Medicines Questionnaire (BMQ) and Adherence Starts with Knowledge (ASK-12) questionnaire were originally developed and validated in Western populations to assess beliefs and barriers to medication adherence. The study aim is to validate the BMQ and ASK-12 questionnaire for use in a Singapore population with early stage breast cancer. English-speaking women on adjuvant endocrine therapy (n = 157) were recruited. The BMQ-Specific showed good internal consistency with structural validity. The internal consistency of BMQ-General and ASK-12 Behaviour scale improved with the new factor structure obtained from exploratory factor analysis. Further studies are needed to confirm these factor structures.
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Neoplasias de la Mama , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Conocimientos, Actitudes y Práctica en Salud , Humanos , Cumplimiento de la Medicación , Reproducibilidad de los Resultados , Encuestas y CuestionariosRESUMEN
Background: Oestrogen receptor positive, human epidermal growth factor receptor-2 (HER2) negative breast cancer (BC) is the most frequently diagnosed BC subtype. Combinations of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with anti-oestrogen therapy have led to improved survival compared with anti-oestrogen therapy alone for advanced/metastatic BC. The evaluation of CDK4/6i in the real-world facilitates treatment planning, insights into the incidence of drug toxicities, dose modifications including dose delays (DDs) and dose reductions (DRs) and improves prognostic accuracy in subgroups, for example geriatric patients, who are under-represented in clinical trials. Methods: This multi-centre study analysed retrospective and prospective data from 456 patients treated with CDK4/6i between January 2015 and December 2020. We examined patient characteristics, variation in prescribing practices, efficacy and toxicity outcomes. Results: In all, 456 patients were included in this study. The median age was 59 (range: 24-92). In total, 85 (19%) were ⩾70 years old. In all, 122 (27%) and 119 (26%) of patients were treated in the first-line and second-line settings, respectively. In total, 25 (5%), 31 (7%) and 145 (32%) of patients had brain, peritoneum and liver metastasis, respectively, at the time of CDK4/6i initiation. On univariate analysis, heavily pre-treated patients and those with distant metastases, involving the liver, brain or peritoneum, had significantly shorter progression-free survival (PFS) and 24-month overall survival (OS). Elderly patients (⩾70) had a shorter PFS; OS results were not mature. Majority of patients (n = 362, 80%) initiated treatment with the United States FDA-approved starting dose of CDK4/6i. In all, 330 (72%) had at least one DD and 217 (48%) patients required at least one DR, but these dose modifications were not associated with poorer survival outcomes. Patients age ⩾70 were more likely to require dose modifications leading to a lower treatment dose. The most common reason for DD/DR was neutropenia (60%) and the incidence of febrile neutropenia was only 2%. Conclusions: Our study indicates CDK4/6i is effective and safe. Age ⩾ 70, distant metastases to liver, peritoneal or brain were negative prognostic factors. Age ⩾ 70 was associated with significantly increased requirement for dose modification; however, this did not impact survival outcomes. These findings provide reassurance that survival outcomes are not adversely affected in elderly patients when DD/DR is indicated.
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BACKGROUND: Varlitinib is a highly potent, small-molecule, pan-HER inhibitor targeting HER1, HER2, and HER4. It has demonstrated activity in gastric, biliary tract, and breast cancers. OBJECTIVE: We conducted a phase Ib dose confirmation study to determine safety and early efficacy signals of varlitinib in combination with chemotherapy (paclitaxel ± carboplatin) ± subcutaneous trastuzumab. METHODS: Eligible patients had advanced or metastatic solid tumors. A 3+3 dose de-escalation study design was used and pharmacokinetic analyses of varlitinib and paclitaxel were performed. RESULTS: Thirty-seven patients were enrolled into eight cohorts with median 4 (0-14) prior lines of palliative systemic therapies. Carboplatin area under the curve 1.5 and paclitaxel 80 mg/m2 weekly with varlitinib 500 mg twice daily continuously was de-escalated over four dose levels to 300 mg twice daily intermittently (4 days on, 3 days off) due to dose-limiting toxicities, most commonly neutropenia, febrile neutropenia, and electrolyte disturbances, with the triplet combination deemed intolerable and unable to be developed further. Varlitinib was then combined with paclitaxel alone; the recommended phase II dose of varlitinib was 300 mg twice daily intermittently. The addition of subcutaneous trastuzumab 600 mg was safe with no dose-limiting toxicities. Thirty-one patients were evaluable for response: 35.5% partial response, 41.9% stable disease. Twenty patients had HER2+ metastatic breast cancer with a median of 4 (0-14) treatment lines, 8/20 continued on single-agent varlitinib after completing chemotherapy for a median of 5.1 (range 2.0-13.3) months. A pharmacokinetic analysis showed that plasma exposure of varlitinib was dose dependent. Varlitinib administration did not significantly affect the maximum concentration or area under the curve of paclitaxel. CONCLUSIONS: The recommended phase II dose of varlitinib with paclitaxel is 300 mg twice daily intermittently dosed. This is active in HER2+ metastatic breast cancer. Subcutaneous trastuzumab can be added safely to varlitinib and paclitaxel. This combination is currently being evaluated as neoadjuvant therapy in HER2+ breast cancer (NCT02396108). CLINICAL TRIAL REGISTRATION: NCT02396108, date of registration: 25 March, 2015.
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Neoplasias de la Mama , Paclitaxel , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Carboplatino/farmacología , Carboplatino/uso terapéutico , Femenino , Humanos , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Resultado del TratamientoRESUMEN
BACKGROUND: Breast cancers are heterogeneous with variable clinical courses and treatment responses. OBJECTIVE: We sought to evaluate dynamic changes in the molecular landscape of HER2-negative tumors treated with chemotherapy and anti-angiogenic agents. PATIENTS AND METHODS: Newly diagnosed HER2-negative breast cancer patients received low-dose sunitinib or bevacizumab prior to four 2-weekly cycles of dose-dense doxorubicin and cyclophosphamide. Tumor biopsies were obtained at baseline, after 2 weeks and after 8 weeks of chemotherapy. Next-generation sequencing was performed to assess for single nucleotide variants (SNVs) and copy number alterations (CNAs) of 440 cancer-related genes (ACTOnco®). Observed genomic changes were correlated with the Miller-Payne histological response to treatment. RESULTS: Thirty-four patients received sunitinib and 18 received bevacizumab. In total, 77% were hormone receptor positive (HER2-/HR+) and 23% were triple negative breast cancers (TNBC). New therapy-induced mutations were infrequent, occurring only in 13%, and appeared early after a single cycle of treatment. Seventy-two percent developed changes in the variant allele frequency (VAF) of pathogenic SNVs; the majority (51%) of these changes occurred early at 2 weeks and were sustained for 8 weeks. Changes in VAF of SNVs were most commonly seen in the PI3K/mTOR/AKT pathway; 13% developed changes in pathogenic mutations, which potentially confer sensitivity to PIK3CA inhibitors. Tumors with poor Miller-Payne response to treatment were less likely to experience changes in VAF of SNVs compared with those with good response (50% [7/14] vs 15% [4/24] had no changes observed at any timepoint, p = 0.029). CONCLUSIONS: Serial molecular profiling identifies early therapy-induced genomic alterations, which may guide future selection of targeted therapies in breast cancer patients who progress after standard chemotherapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT02790580 (first posted June 6, 2016).
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Inhibidores de la Angiogénesis/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapéutico , Sunitinib/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
PURPOSE: RET is an estrogen response gene with preclinical studies demonstrating cross-talk between the RET and estrogen receptor (ER) pathways. We investigate the role of lenvatinib, a multikinase inhibitor with potent activity against RET, in patients with metastatic breast cancer. PATIENTS AND METHODS: Patients with advanced ER+/HER2- breast cancer were treated with lenvatinib plus letrozole in a phase Ib/II trial. Primary objectives included safety and recommended phase II dose (RP2D) determination in phase Ib, and objective response rates (ORR) in phase II dose expansion. RESULTS: Sixteen patients were recruited in dose finding, where deescalating doses of lenvatinib from 20 to 14 mg were investigated. Lenvatinib 14 mg plus letrozole 2.5 mg daily was determined as RP2D. Thirty-one patients with 5 median lines of prior therapy in the metastatic setting (range, 0-11) were recruited in dose expansion. In this cohort, ORR was 23.3% [95% confidence interval (CI) 9.9%-42.3%], with median duration of response (DoR) of 6.9 months [interquartile range (IQR) 5.9 to 13.1]. Clinical benefit rate ≥6 months (CBR) was 50.0% (95% CI, 31.3%-68.7%). Similar efficacy was observed in the subgroup of 25 patients who progressed on prior CDK4/6 inhibitor therapy [ORR 20.0% (95% CI, 6.8%-40.7%), median DoR 6.9 months (IQR 5.9-13.1), and CBR 52.0% (95% CI, 31.3%-72.2%)]. Pharmacodynamic studies showed target modulation, with paired tumor biopsies indicating downregulation of RET/pERK and improved vascular normalization index. CONCLUSIONS: Lenvatinib plus letrozole had manageable toxicity, with target engagement and preliminary antitumor activity observed, supporting further assessment in randomized studies.
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Neoplasias de la Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Letrozol , Compuestos de Fenilurea , Posmenopausia , Quinolinas , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismoRESUMEN
S-1 is an oral fluoropyrimidine anti-neoplastic agent that is converted by CYP2A6 to 5-fluorouracil (5FU). We prospectively studied the pharmacokinetics and pharmacodynamics of S-1 in two groups of East Asian and Caucasian patients with solid malignancy refractory to standard chemotherapy, or for which 5FU was indicated, to elucidate differences in relation to CYP2A6 genotype and phenotype. S-1 was given orally at 30 mg/m(2) b.i.d. for 14 days every 21 days. Dose normalized AUC(0-48 h) for tegafur (P = 0.05) and gimeracil (P = 0.036) were higher in East Asians; conversely, AUC(0-48 h) of fluoro-ß-alanine was higher in Caucasians (P = 0.044). Exposure to 5FU was similar in both groups (P = 0.967). Mean cotinine:nicotine ratio was 54% higher in the Caucasian group (P = 0.03), and correlated with oral clearance of tegafur (r = 0.59; P = 0.002). Grade 3/4 gastrointestinal toxicities were more common in Caucasians than Asians (21%vs 0%). Treatment with S-1 yields no significant difference in 5FU exposure between Caucasians and East Asians.
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Antimetabolitos Antineoplásicos/farmacocinética , Ácido Oxónico/farmacocinética , Tegafur/farmacocinética , Adulto , Anciano , Antimetabolitos Antineoplásicos/efectos adversos , Área Bajo la Curva , Hidrocarburo de Aril Hidroxilasas/genética , Pueblo Asiatico/genética , Citocromo P-450 CYP2A6 , Combinación de Medicamentos , Asia Oriental , Femenino , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Neoplasias/tratamiento farmacológico , Ácido Oxónico/efectos adversos , Fenotipo , Tegafur/efectos adversos , Población Blanca/genéticaRESUMEN
BACKGROUND: The optimal treatment and molecular landscape of recurrent clear cell carcinoma of the vulva (VCCC) are unknown. No reported data exist regarding the efficacy of anti-programmed death 1 (PD-1) immune checkpoint inhibition in VCCC. We report on a patient with chemotherapy-refractory recurrent VCCC, who was found to have high tumor programmed death-ligand 1 (PD-L1) combined positive score (CPS), and subsequently experienced a durable partial response (PR), after treatment with off-label fifth-line pembrolizumab. CASE PRESENTATION: A forty-year-old Filipino woman presented to our center with recurrent VCCC that had progressed on multiple prior lines of cytotoxic chemotherapy. She had a large 25 cm fungating left groin tumor causing marked lower limb lymphedema, pain and limited mobility. PD-L1 CPS by immunohistochemistry was 45. She was treated with off-label pembrolizumab monotherapy and had a dramatic clinical, biochemical and radiological partial response. The progression-free survival of this patient's VCCC after treatment with pembrolizumab, defined as the time from initiation of pembrolizumab until disease progression (by Response Evaluation Criteria in Solid Tumors (version 1.1)), was 8 months. While receiving pembrolizumab, she was diagnosed with concurrent secondary myelodysplastic syndrome with excess blasts (MDS-EB), thought to be related to her prior exposure to multiple lines of cytotoxic chemotherapy. This eventually progressed to acute myeloid leukemia (AML), leading to her demise. Overall survival from time of initiation of pembrolizumab till death was 16 months. CONCLUSION: Pembrolizumab was active in this patient with chemotherapy-refractory VCCC which harbored high PD-L1 CPS. Further studies to determine the role of immune check-point blockade in the treatment of VCCC are warranted.
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PURPOSE: Low-dose fractionated whole abdominal radiation therapy (LDFWART) has synergistic activity with paclitaxel in preclinical models. The aim of this phase 1 trial was to determine the recommended phase 2 dose and preliminary activity of weekly paclitaxel (wP) concurrent with LDFWART in patients with platinum-resistant ovarian cancer (PROC). METHODS AND MATERIALS: Patients were enrolled at de-escalating dose levels of wP (part A), starting at 80 mg/m2, concurrent with fixed-dose LDFWART delivered in 60 cGy fractions twice-daily, 2 days per week, for 6 continuous weeks. After completing the 6-week course of wP + LDFWART, patients received wP until disease progression. Dose-limiting toxicity was evaluated during the first 3 weeks of wP + LDFWART. At wP (80 mg/m2) + LDFWART, no dose-limiting toxicities were observed; this was the established maximum tolerated dose. The trial was expanded (part B) with 7 additional patients with platinum-resistant, high-grade serous ovarian cancer to confirm toxicity and activity. RESULTS: A total of 10 heavily pretreated patients were recruited (3 patients to part A, 7 patients to part B). They had received a median of 5 prior lines of therapy, and 70% of patients had received prior wP; 60% of patients completed 6 weeks of wP + LDFWART. Common related grade ≥3 adverse events were neutropenia (60%) and anemia (30%). Median progression-free survival was 3.2 months, and overall survival was 13.5 months. Of patients evaluable for response, 33% (3 of 9) achieved confirmed biochemical response (CA125 decrease >50% from baseline), 11% (1) achieved a partial response, and 5 patients had stable disease, giving a disease control rate of 66.7% (6 of 9). Four patients had durable disease control of ≥12 weeks, completing 12 to 21 weeks of wP. CONCLUSIONS: The recommended phase 2 dose of wP + LDFWART for 6 weeks is 80 mg/m2. Encouraging efficacy in heavily pretreated PROC patients was observed, suggesting that further development of this therapeutic strategy in PROC should be considered.
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Antineoplásicos Fitogénicos/administración & dosificación , Quimioradioterapia/métodos , Neoplasias Ováricas/terapia , Paclitaxel/administración & dosificación , Abdomen , Adulto , Anciano , Anemia/inducido químicamente , Antineoplásicos Fitogénicos/efectos adversos , Progresión de la Enfermedad , Fraccionamiento de la Dosis de Radiación , Esquema de Medicación , Resistencia a Antineoplásicos , Femenino , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Neutropenia/etiología , Neoplasias Ováricas/mortalidad , Paclitaxel/efectos adversos , Medición de Resultados Informados por el Paciente , Compuestos de Platino/uso terapéutico , Supervivencia sin ProgresiónRESUMEN
BACKGROUND: Patients with metastatic breast cancer (MBC) are usually exposed to both anthracyclines and taxanes during neoadjuvant or adjuvant treatment of primary breast cancer or during initial therapy of MBC. We investigate the combination of gemcitabine and carboplatin in MBC with prior exposure to both anthracyclines and taxanes. PATIENTS AND METHODS: MBC patients previously treated with anthracyclines and taxanes were enrolled in a single tertiary center phase II study. Treatment consisted of gemcitabine (1,000 mg/m(2) I.V on days 1 and 8) and carboplatin (AUC 5 I.V on day 1) administered every 3 weeks. Results 41 patients were recruited. Objective response rate was 39% including 1 complete response (2%) and 15 partial responses (37%). Twelve patients (29%) had stable disease. Median time to progression was 4.6 months (95% CI 3.3-5.9 months) and median overall survival 10.5 months (95% CI 7.6-13.4 months). Grade 3 & 4 hematological toxicities included neutropenia (58%), febrile neutropenia (15%), anemia (12%) and thrombocytopenia (49%), including 7% who required platelet transfusions. Non-hematological toxicity was rarely severe. 56% of patients required at least one dose reduction; the mean relative dose intensity for gemcitabine and carboplatin were 0.82 (range 0.5-1.0) and 0.95 (range 0.75-1.00) respectively, with no difference in dose intensity between responders and non-responders. CONCLUSION: Gemcitabine combined with carboplatin has promising efficacy in MBC with prior treatment with anthracyclines and taxanes but has significant haematological toxicities requiring dose modifications. The regimen may be modified to gemcitabine 800 mg/m(2) days 1 and 8 to improve tolerability.
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Antraciclinas/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Carboplatino/uso terapéutico , Desoxicitidina/análogos & derivados , Taxoides/uso terapéutico , Adulto , Anciano , Antineoplásicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carboplatino/efectos adversos , Desoxicitidina/efectos adversos , Desoxicitidina/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Resultado del Tratamiento , GemcitabinaRESUMEN
Endometrial cancer is one of the gynaecological cancers that carries good overall prognosis because it is often detected at early stages of disease. The International Federation of Gynecology and Obstetrics replaced clinical staging with surgical staging in 1988 and updated the system in 2009. Controversies remain regarding the recommended screening protocol for women with a high risk of endometrial cancer, the role and benefit of retroperitoneal lymph-node dissection, the necessity of ovarian resection, the benefit and type of adjuvant radiation therapy, and the safety of hormone-replacement therapy after treatment. This article reviews the available evidence for optimum management of endometrial cancer and how management strategies can be applied in Asian countries with different levels of health-care resource availability and economic development. An overview of the literature for endometrial-cancer screening, diagnosis, and management is discussed. Consensus statements are formulated on the basis of basic, limited, enhanced, and maximum health-care resource availability, using the framework provided by the Breast Health Global Initiative.
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Países en Desarrollo , Neoplasias Endometriales/terapia , Procedimientos Quirúrgicos Ginecológicos , Terapia de Reemplazo de Hormonas , Oncología Médica , Asia/epidemiología , Quimioterapia Adyuvante , Congresos como Asunto , Análisis Costo-Beneficio , Países en Desarrollo/economía , Costos de los Medicamentos , Diagnóstico Precoz , Neoplasias Endometriales/diagnóstico , Neoplasias Endometriales/economía , Neoplasias Endometriales/mortalidad , Medicina Basada en la Evidencia , Femenino , Adhesión a Directriz , Procedimientos Quirúrgicos Ginecológicos/economía , Costos de la Atención en Salud , Accesibilidad a los Servicios de Salud , Disparidades en Atención de Salud , Terapia de Reemplazo de Hormonas/efectos adversos , Terapia de Reemplazo de Hormonas/economía , Humanos , Escisión del Ganglio Linfático , Tamizaje Masivo , Oncología Médica/economía , Oncología Médica/normas , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Radioterapia Adyuvante , Medición de Riesgo , Resultado del TratamientoRESUMEN
BACKGROUND: Medication adherence is crucial for improving clinical outcomes in the treatment of patients. We evaluate the effect of short message service (SMS) reminder on medication adherence and serum hormones in patients with breast cancer on aromatase inhibitors. METHODS: An open-label, multi-centre, prospective randomised controlled trial of SMS versus Standard Care was conducted. Medication adherence was assessed via self-report using the Simplified Medication Adherence Questionnaire at baseline, 6 month, and 1 year. Androstenedione, estradiol, and estrone were measured at baseline and 1 year. The χ2 test and mixed effects logistic regression was performed to compare medication adherence between groups. Difference in androstenedione and estrone levels were assessed using analysis of covariance, whereas χ2 test and logistic regression was used for estradiol. Analysis was based on intention-to-treat. RESULTS: A total of 244 patients were randomised to receive weekly SMS reminder (n = 123) or Standard Care (n = 121) between May 2015 and December 2018. The odds of adherence was higher at 6-month in SMS (OR = 1.78, 95% CI 1.04-3.05, p = 0.034), and not significantly different at 1-year (OR = 1.15, 95% CI: 0.67-1.96 p = 0.617). Mixed effects logistic regression analysis showed higher odds of adherence in SMS over the 1-year period (OR = 2.35, 95% CI: 1.01-5.49, p = 0.048). There was no difference in serum hormone levels between groups. CONCLUSION: SMS reminder improved medication adherence in the short-term but had no effect on serum hormones levels in the longer term. Future studies could investigate the use of tailored SMS intervention according to patient preference to improve its sustainability.