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A critical shortage of skilled healthcare workers is a primary cause of disparate global cancer outcomes. We report participant evaluation of a multidisciplinary preceptorship program. In collaboration with the city of Kumasi, Ghana, Mayo Clinic and the City Cancer Challenge hosted a preceptorship program for comprehensive multidisciplinary breast and cervix cancer training. A total of 14 healthcare workers from Kumasi received two weeks of training at Mayo Clinic in November and December 2021. Each participant and preceptor were requested to complete an anonymous post-participation survey. Of the 14 trainee participants, 10 (71%) completed the survey. All respondents found the program "valuable and applicable to their clinical practice." Ninety percent reported they were able to "review effective and critical elements in the development and expansion of the multidisciplinary team" and able to "solve practical clinical cases as a team". General themes of satisfaction included: (1) organization and administration, (2) clinical observations and demonstrations, (3) guidelines development, and (4) recognizing the central importance of cultivating a team-based approach. Of the 40 preceptors, 16 (40%) completed the survey. All respondents reported they felt the training would meaningfully "influence patient care in Ghana", that participation "added value or joy to their clinical practice," and all wished to "participate in future preceptorship programs". After a focused two-week program, trainees reported high satisfaction, usefulness from observing specialized cancer care, and value in closely observing a multidisciplinary oncology team. Preceptors reported the experience added joy and perspective to their clinical practice and wished to participate in future programs.
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Oncologia , Preceptoria , Humanos , Gana , Oncologia/educação , Feminino , Pessoal de Saúde/educação , Equipe de Assistência ao Paciente , Inquéritos e Questionários , Masculino , Avaliação de Programas e Projetos de Saúde , Adulto , Neoplasias da MamaRESUMO
PURPOSE: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6is), in combination with endocrine therapy (ET), are standard either in the first (1L) or second-line (2L) setting for the treatment of hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC). However, the optimal sequencing of treatments after progression on CDK4/6i remains unknown. We performed a single-institution analysis to identify treatments and outcomes after progression on a CDK4/6i. METHODS: We identified patients with HR-positive, HER2-negative MBC prescribed a CDK4/6i in the 1L or 2L settings from December 2014 to February 2018 at Mayo Clinic in Rochester, Minnesota. Outcomes were collected through September 30, 2020. RESULTS: Palbociclib, in combination with letrozole or fulvestrant, was the most prescribed CDK4/6i. The 1L and 2L CDK4/6i cohorts exhibited comparable overall survival (OS), but progression-free survival (PFS) was longer in the 1L than the 2L cohort [28.2 months (95% CI 19.6-34.9) vs 19.8 months (95% CI 15.7-29.6)]. The most common post-CDK4/6i treatments were PI3K/mTOR inhibitors (PI3K/mTORi), single-agent ET, or chemotherapy. PFS in the 1L CDK4/6i cohort following PI3K/mTORi was 8.5 months (95% CI 5.5 months-NE), single-agent ET was 6.0 months (95% CI 3.3-14.0 months), and chemotherapy PFS was 5.4 months (95% CI 3.3 months-NE). CONCLUSIONS: Following progression on a CDK 4/6i, mPFS was short, with similar PFS times comparing chemotherapy and ET, with slightly longer PFS for targeted strategies (PI3K/mTOR). These results highlight a major need to better understand the mechanisms of CDK4/6i resistance and identify new therapeutic strategies for these patients.
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Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Feminino , Fulvestranto/uso terapêutico , Humanos , Letrozol/uso terapêutico , Fosfatidilinositol 3-Quinases , Inibidores de Proteínas Quinases , Receptor ErbB-2/genética , Estudos Retrospectivos , Serina-Treonina Quinases TORRESUMO
PURPOSE: We previously reported that postmenopausal women with estrogen receptor-α-positive breast cancer receiving adjuvant anastrozole 1 mg/day (ANA1) with estrone (E1) ≥1.3 pg/mL and estradiol (E2) ≥0.5 pg/mL [inadequate estrogen suppression (IES)] had a threefold increased risk of a breast cancer event. The objective of this study was to determine if increasing anastrozole to 10 mg/day (ANA10) could result in adequate estrogen suppression (AES: E1 <1.3 pg/mL and/or E2 <0.5 pg/mL) among those with IES on ANA1. PATIENTS AND METHODS: Postmenopausal women with estrogen receptor-α-positive breast cancer planning to receive adjuvant ANA1 were eligible. E1 and E2 were assessed pre- and post-8 to 10 weeks of ANA1. Those with IES were switched to 8- to 10-week cycles of ANA10 followed by letrozole 2.5 mg/day. E1 and E2 were assessed after each cycle. Anastrozole concentrations were measured post-ANA1 and post-ANA10. Primary analyses included patients who documented taking at least 80% of the planned treatment (adherent cohort). RESULTS: In total, 132 (84.6%) of 156 eligible patients were ANA1 adherent. IES occurred in 40 (30.3%) adherent patients. Twenty-five (78.1%) of 32 patients who began ANA10 were adherent, and AES was achieved in 19 (76.0%; 90% confidence interval, 58.1%-89.0%) patients. Anastrozole concentrations post-ANA1 and post-ANA10 did not differ by estrogen suppression status among adherent patients. AES was maintained/attained in 21 (91.3%) of 23 letrozole-adherent patients. CONCLUSIONS: Approximately 30% of ANA1-adherent patients had IES. Among those who switched to ANA10 and were adherent, 76% had AES. Further studies are required to validate emerging data that ANA1 results in IES for some patients and to determine the clinical benefit of switching to ANA10 or an alternative aromatase inhibitor.
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Anastrozol , Neoplasias da Mama , Nitrilas , Pós-Menopausa , Triazóis , Humanos , Anastrozol/administração & dosagem , Anastrozol/uso terapêutico , Anastrozol/efeitos adversos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pessoa de Meia-Idade , Idoso , Triazóis/administração & dosagem , Triazóis/efeitos adversos , Nitrilas/administração & dosagem , Nitrilas/efeitos adversos , Estrogênios/administração & dosagem , Estadiamento de Neoplasias , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Antineoplásicos Hormonais/uso terapêutico , Estudos Prospectivos , Estradiol/administração & dosagem , Estrona/sangue , Estrona/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Inibidores da Aromatase/efeitos adversosRESUMO
Importance: Aurora A kinase (AURKA) activation, related in part to AURKA amplification and variants, is associated with downregulation of estrogen receptor (ER) α expression, endocrine resistance, and implicated in cyclin-dependent kinase 4/6 inhibitor (CDK 4/6i) resistance. Alisertib, a selective AURKA inhibitor, upregulates ERα and restores endocrine sensitivity in preclinical metastatic breast cancer (MBC) models. The safety and preliminary efficacy of alisertib was demonstrated in early-phase trials; however, its activity in CDK 4/6i-resistant MBC is unknown. Objective: To assess the effect of adding fulvestrant to alisertib on objective tumor response rates (ORRs) in endocrine-resistant MBC. Design, Setting, and Participants: This phase 2 randomized clinical trial was conducted through the Translational Breast Cancer Research Consortium, which enrolled participants from July 2017 to November 2019. Postmenopausal women with endocrine-resistant, ERBB2 (formerly HER2)-negative MBC who were previously treated with fulvestrant were eligible. Stratification factors included prior treatment with CDK 4/6i, baseline metastatic tumor ERα level measurement (<10%, ≥10%), and primary or secondary endocrine resistance. Among 114 preregistered patients, 96 (84.2%) registered and 91 (79.8%) were evaluable for the primary end point. Data analysis began after January 10, 2022. Interventions: Alisertib, 50 mg, oral, daily on days 1 to 3, 8 to 10, and 15 to 17 of a 28-day cycle (arm 1) or alisertib same dose/schedule with standard-dose fulvestrant (arm 2). Main Outcomes and Measures: Improvement in ORR in arm 2 of at least 20% greater than arm 1 when the expected ORR for arm 1 was 20%. Results: All 91 evaluable patients (mean [SD] age, 58.5 [11.3] years; 1 American Indian/Alaskan Native [1.1%], 2 Asian [2.2%], 6 Black/African American [6.6%], 5 Hispanic [5.5%], and 79 [86.8%] White individuals; arm 1, 46 [50.5%]; arm 2, 45 [49.5%]) had received prior treatment with CDK 4/6i. The ORR was 19.6%; (90% CI, 10.6%-31.7%) for arm 1 and 20.0% (90% CI, 10.9%-32.3%) for arm 2. In arm 1, the 24-week clinical benefit rate and median progression-free survival time were 41.3% (90% CI, 29.0%-54.5%) and 5.6 months (95% CI, 3.9-10.0), respectively, and in arm 2 they were 28.9% (90% CI, 18.0%-42.0%) and 5.4 months (95% CI, 3.9-7.8), respectively. The most common grade 3 or higher adverse events attributed to alisertib were neutropenia (41.8%) and anemia (13.2%). Reasons for discontinuing treatment were disease progression (arm 1, 38 [82.6%]; arm 2, 31 [68.9%]) and toxic effects or refusal (arm 1, 5 [10.9%]; arm 2, 12 [26.7%]). Conclusions and Relevance: This randomized clinical trial found that adding fulvestrant to treatment with alisertib did not increase ORR or PFS; however, promising clinical activity was observed with alisertib monotherapy among patients with endocrine-resistant and CDK 4/6i-resistant MBC. The overall safety profile was tolerable. Trial Registration: ClinicalTrials.gov Identifier: NCT02860000.
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Neoplasias da Mama , Humanos , Feminino , Pessoa de Meia-Idade , Fulvestranto , Neoplasias da Mama/patologia , Receptor alfa de Estrogênio , Aurora Quinase A/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
OBJECTIVE: To evaluate the efficacy and biological effects of the gemcitabine/tanespimycin combination in patients with advanced ovarian and peritoneal cancer. To assess the effect of tanespimycin on tumor cells, levels of the chaperone proteins HSP90 and HSP70 were examined in peripheral blood mononuclear cells (PBMC) and paired tumor biopsy lysates. METHODS: Two-cohort phase II clinical trial. Patients were grouped according to prior gemcitabine therapy. All participants received tanespimycin 154 mg/m(2) on days 1 and 9 of cycle 1 and days 2 and 9 of subsequent cycles. Patients also received gemcitabine 750 mg/m(2) on day 8 of the first treatment cycle and days 1 and 8 of subsequent cycles. RESULTS: The tanespimycin/gemcitabine combination induced a partial response in 1 gemcitabine naïve patient and no partial responses in gemcitabine resistant patients. Stable disease was seen in 6 patients (2 gemcitabine naïve and 4 gemcitabine resistant). The most common toxicities were hematologic (anemia and neutropenia) as well as nausea and vomiting. Immunoblotting demonstrated limited upregulation of HSP70 but little or no change in levels of most client proteins in PBMC and paired tumor samples. CONCLUSIONS: Although well tolerated, the tanespimycin/gemcitabine combination exhibited limited anticancer activity in patients with advanced epithelial ovarian and primary peritoneal carcinoma, perhaps because of failure to significantly downregulate the client proteins at clinically achievable exposures.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Epiteliais e Glandulares/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzoquinonas/administração & dosagem , Benzoquinonas/efeitos adversos , Biomarcadores Tumorais/metabolismo , Carcinoma Epitelial do Ovário , Linhagem Celular Tumoral , Estudos de Coortes , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Feminino , Proteínas de Choque Térmico HSP70/metabolismo , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Lactamas Macrocíclicas/administração & dosagem , Lactamas Macrocíclicas/efeitos adversos , Pessoa de Meia-Idade , Neoplasias Epiteliais e Glandulares/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Peritoneais/metabolismo , Taxa de Sobrevida , GencitabinaRESUMO
PURPOSE: Based upon promising preclinical and phase 1 trial results, combined flavopiridol and cisplatin therapy was evaluated in patients with ovarian and primary peritoneal cancers. METHODS: A two cohort phase 2 trial of cisplatin (60 mg/m2 IV) immediately followed by flavopiridol (100 mg/m2 IV, 24 h infusion; 21 day cycles) was undertaken in patients with recurrent platin-sensitive or platin-resistant disease (progression>vs. ≤6 months following prior platin-based therapy). Measurable disease (RECIST)--or evaluable disease plus CA125>2X post-treatment nadir--and ECOG performance≤2 were required. RESULTS: Forty-five patients were enrolled between December 23, 2004 and February 25, 2010: 40 platin-resistant (Group 1), and 5 platin-sensitive (Group 2). In Group 1, the median number of treatment cycles was 3 (range 2-12). Only 10% of patients incurred grade 4 toxicities, but grade 3 toxicities were common (65%): neutropenia (17.5%); nausea (12.5%); vomiting, fatigue, thrombosis, anemia (10% each). Seven patients (17.5%) achieved a confirmed response (1 CR, 6 PR; median duration 118 days); ten additional patients (25%) attained maintained stable disease. Median time to progression was 4.3 months; overall survival was 16.1 months. Pilot translational studies assessed ascites flavopiridol level; surrogate marker studies were uninformative. In Group 2, although 4 of 5 patients responded (2 confirmed PRs with median time to progression, 10.8 months and median overall survival 20.6 months) the cohort was closed due to poor accrual. CONCLUSIONS: The assessed flavopiridol and cisplatin regimen displayed clinical activity in platin resistant and sensitive ovarian/primary peritoneal cancers, meriting further study.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Sobrevivência Celular/efeitos dos fármacos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Estudos de Coortes , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Flavonoides/administração & dosagem , Flavonoides/efeitos adversos , Humanos , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Neoplasias Peritoneais/patologia , Piperidinas/administração & dosagem , Piperidinas/efeitos adversos , Adulto JovemRESUMO
OBJECTIVE: Resistance to chemotherapy is a major challenge in the treatment of ovarian/peritoneal cancer. One purported mechanism of topotecan resistance is the breast cancer resistance protein (BCRP) and P-glycoprotein (Pgp). We designed a phase II clinical trial evaluating the efficacy and adverse event profile of concomitant topotecan and lapatinib, a small molecule pan-erbB inhibitor that can block BCRP/Pgp efflux of topotecan. METHODS: Patients with platinum-refractory or resistant epithelial ovarian/peritoneal cancer were treated with topotecan 3.2 mg/m² IV on Day 1, 8 and 15 and lapatinib 1250 mg PO daily, continuously in 28 day cycles. The primary endpoint was response rate. For correlative studies, archived tissue was assessed for expression of EGFR, HER2, HIF-1α, CD31, and BCRP. RESULTS: Eighteen patients were enrolled and treated. Four experienced evidence of clinical benefit: one partial response and three with stable disease. Using a two-stage Simon design, the trial was stopped after the first stage due to insufficient activity. Grades 3+ and 4+ adverse events (AE) were experienced in 14 and 4 patients, respectively. The most common grade 3/4 AE were neutropenia (56%), thrombocytopenia (28%), and diarrhea (22%). CONCLUSIONS: The combination of lapatinib plus topotecan for the treatment of platinum refractory/resistant epithelial ovarian cancer lacks sufficient activity to warrant further investigation. In particular, hematologic adverse events were substantial. Expression of correlative study markers did not reveal patterns of predicted benefit or toxicity. Disruption of erbB signaling and BCRP/Pgp efflux with lapatinib was insufficient for overcoming topotecan resistance, suggesting alternative mechanisms of resistance are involved.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Peritoneais/tratamento farmacológico , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/biossíntese , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/metabolismo , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB/biossíntese , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Lapatinib , Pessoa de Meia-Idade , Proteínas de Neoplasias/biossíntese , Compostos Organoplatínicos/farmacologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossíntese , Quinazolinas/administração & dosagem , Quinazolinas/efeitos adversos , Receptor ErbB-2/biossíntese , Taxa de Sobrevida , Topotecan/administração & dosagem , Topotecan/efeitos adversosRESUMO
This study examined how the lay electronic media covers poly-ADP-ribose polymerase, or "PARP," inhibitors, a class of cancer agents currently under clinical investigation. Of 771 internet links, 51 targeted the lay public. Independent review by two investigators yielded the following categorizations: 36 (71%) were "overly positive", 15 (29%) "neutral", and none "overly negative". "Overly positive" articles used: (l) overstated benefit, (2) included quotations from enthusiastic scientists, and (3) discussed single or small patient subsets. They used such phrases as "the holy grail of cancer research", "the most exciting development in cancer research in a decade or more . it could save thousands of lives", and "we were surprised and delighted . it's the kind of thing you don't really think will happen". Healthcare providers should be aware of the foregoing when discussing PARP inhibitors-and perhaps other novel therapies-with cancer patients.
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Publicidade , Antineoplásicos/uso terapêutico , Comportamento de Escolha , Inibidores Enzimáticos/uso terapêutico , Neoplasias/tratamento farmacológico , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Internet , Neoplasias/enzimologia , TelevisãoRESUMO
PURPOSE: To determine the sensitivity and specificity of genetic testing criteria for the detection of germline pathogenic variants in women with breast cancer. MATERIALS AND METHODS: Women with breast cancer enrolled in a breast cancer registry at a tertiary cancer center between 2000 and 2016 were evaluated for germline pathogenic variants in 9 breast cancer predisposition genes (ATM, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, and TP53). The performance of the National Comprehensive Cancer Network (NCCN) hereditary cancer testing criteria was evaluated relative to testing of all women as recommended by the American Society of Breast Surgeons. RESULTS: Of 3,907 women, 1,872 (47.9%) meeting NCCN criteria were more likely to carry a pathogenic variant in 9 predisposition genes compared with women not meeting criteria (9.0% v 3.5%; P < .001). Of those not meeting criteria (n = 2,035), 14 (0.7%) had pathogenic variants in BRCA1 or BRCA2. The sensitivity of NCCN criteria was 70% for 9 predisposition genes and 87% for BRCA1 and BRCA2, with a specificity of 53%. Expansion of the NCCN criteria to include all women diagnosed with breast cancer at ≤ 65 years of age achieved > 90% sensitivity for the 9 predisposition genes and > 98% sensitivity for BRCA1 and BRCA2. CONCLUSION: A substantial proportion of women with breast cancer carrying germline pathogenic variants in predisposition genes do not qualify for testing by NCCN criteria. Expansion of NCCN criteria to include all women diagnosed at ≤ 65 years of age improves the sensitivity of the selection criteria without requiring testing of all women with breast cancer.
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Neoplasias da Mama/genética , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Mutação em Linhagem Germinativa , Hospitais , Adulto , Idoso , Idoso de 80 Anos ou mais , Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/prevenção & controle , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Feminino , Humanos , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Adulto JovemRESUMO
The 21-gene Recurrence Score (RS) assay is prognostic and predictive of adjuvant chemotherapy benefit in node positive (N+) breast cancer (BC). We sought to evaluate use patterns of RS assay in N+, ER+/HER2- BC and the impact of RS on recommendations for adjuvant chemotherapy. Patients with T1-T4c,N1mi-N3, ER+/HER2- BC diagnosed 2010-2013 in the National Cancer Database were analyzed. Multivariable logistic regression assessed factors influencing RS testing and chemotherapy recommendations based on RS. Among 72,897 patients, RS was obtained in 20.6%, increasing from 15.0% in 2010 to 24.5% in 2013 (p < 0.001). RS testing was most common in N1mi (43.7%) followed by N1 (22.1%) and rare in N2/N3 (3.3%). Of the 12,536 with quantitative RS results, 61.1% were low RS, 32.3% intermediate RS and 6.6% high RS. Chemotherapy was recommended less frequently in patients with RS testing (50.4%) vs. those not tested (81.0%, p < 0.001). In N1mi/N1 patients, chemotherapy recommendation varied by RS; however, in N2/N3 patients, chemotherapy was recommended in the majority (70.9-87.5%) regardless of RS. Most patients (>85%) with RS ≥ 26 were recommended chemotherapy regardless of nodal stage. For patients with RS < 26, chemotherapy recommendations increased with higher N and T stage, grade, and younger age (p < 0.001). Histology was not associated with chemotherapy recommendation in any RS subset. The RS assay is frequently and increasingly being used for decision making in node positive ER+/HER2- breast cancer patients and its use is associated with lower rates of adjuvant chemotherapy.
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PURPOSE: This phase I study was conducted to determine the safety, tolerability and maximum tolerated dose of the combination of celecoxib, a selective cyclooxygenase-2 inhibitor, with docetaxel and irinotecan, in patients with advanced solid tumors. PATIENTS AND METHODS: Patients with solid tumors received one of three escalating dose levels of daily celecoxib in combination with docetaxel and irinotecan administered on days 1 and 8 of an every 21-day cycle. Toxicities were graded by the National Cancer Institute Common Toxicity Criteria (NCI CTC) and recorded as maximum grade per patient for each treatment cycle. RESULTS: A total of 19 patients received 90 cycles of treatment through three dose levels. Dose-limiting toxicities were nausea and diarrhea. The most common treatment-related toxicities in all cycles of treatment were alopecia, fatigue, diarrhea, nausea, vomiting, anemia, anorexia, and edema.. The maximum tolerated dose was established at celecoxib 400 mg twice a day continuously, weekly docetaxel 30 mg/m2 and irinotecan 50 mg/m2 for 2 weeks every 21 days. Disease stabilization (five or more cycles) was documented in eight patients. CONCLUSION: The combination of celecoxib with docetaxel and irinotecan did not ameliorate irinotecan-induced diarrhea. Although prolonged disease stabilization was achieved in some patients, we do not recommend combining celecoxib with docetaxel and irinotecan because of lack of activity and the side effect profile of this combination.
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Antineoplásicos Fitogênicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Camptotecina/análogos & derivados , Inibidores de Ciclo-Oxigenase/uso terapêutico , Neoplasias/tratamento farmacológico , Pirazóis/uso terapêutico , Sulfonamidas/uso terapêutico , Taxoides/uso terapêutico , Adulto , Idoso , Camptotecina/uso terapêutico , Celecoxib , Diarreia/induzido quimicamente , Docetaxel , Relação Dose-Resposta a Droga , Feminino , Humanos , Irinotecano , Masculino , Pessoa de Meia-Idade , Náusea/induzido quimicamente , Neoplasias/patologia , Resultado do TratamentoRESUMO
Pegfilgrastim (Neulasta) is a recombinant filgrastim (human granulocyte colony-stimulating factor (G-CSF)) attached to a polyethylene glycol (PEG) molecule and is given as part of chemotherapy regimens that are associated with significant myelosuppression and risk for febrile neutropenia. Prescribing information available on manufacturer's website for the drug warns us about possible severe sickle cell crises related to the medication but does not report the actual incidence or the use in patients with sickle cell trait. Caution is advised when using it in patients with sickle cell disease. Here we present a case of a Caucasian female with known sickle cell trait (SCT) with no prior complications who developed a presumed sickle cell crisis after getting Neulasta, as a part of the chemotherapy regimen used to treat her breast cancer. Based on our literature review, this appears to be the first case report of a patient with SCT developing a sickle cell crisis with the pegylated form of recombinant filgrastim. Given the dearth of literature regarding the use of G-CSF and its related pegylated forms in patients with sickle cell anemia and sickle cell trait, a discussion of potential mechanisms and review of current literature and guidelines is also presented.
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BACKGROUND: Invasive ovarian cancer is a significant cause of gynecologic cancer mortality. METHODS: We examined whether this mortality was associated with inherited variation in approximately 170 candidate genes/regions [993 single-nucleotide polymorphisms (SNPs)] in a multistage analysis based initially on 312 Mayo Clinic cases (172 deaths). Additional analyses used The Cancer Genome Atlas (TCGA; 127 cases, 62 deaths). For the most compelling gene, we immunostained Mayo Clinic tissue microarrays (TMA, 326 cases) and conducted consortium-based SNP replication analysis (2,560 cases, 1,046 deaths). RESULTS: The strongest initial mortality association was in HGF (hepatocyte growth factor) at rs1800793 (HR = 1.7, 95% CI = 1.3-2.2, P = 2.0 × 10(-5)) and with overall variation in HGF (gene-level test, P = 3.7 × 10(-4)). Analysis of TCGA data revealed consistent associations [e.g., rs5745709 (r(2) = 0.96 with rs1800793): TCGA HR = 2.4, CI = 1.4-4.1, P = 2.2 × 10(-3); Mayo Clinic + TCGA HR = 1.6, CI = 1.3-1.9, P = 7.0 × 10(-5)] and suggested genotype correlation with reduced HGF mRNA levels (P = 0.01). In Mayo Clinic TMAs, protein levels of HGF, its receptor MET (C-MET), and phospho-MET were not associated with genotype and did not serve as an intermediate phenotype; however, phospho-MET was associated with reduced mortality (P = 0.01) likely due to higher expression in early-stage disease. In eight additional ovarian cancer case series, HGF rs5745709 was not associated with mortality (HR = 1.0, CI = 0.9-1.1, P = 0.87). CONCLUSIONS: We conclude that although HGF signaling is critical to migration, invasion, and apoptosis, it is unlikely that HGF genetic variation plays a major role in ovarian cancer mortality. Furthermore, any minor role is not related to genetically-determined expression. IMPACT: Our study shows the utility of multiple data types and multiple data sets in observational studies.
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Fator de Crescimento de Hepatócito/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Feminino , Genótipo , Fator de Crescimento de Hepatócito/metabolismo , Humanos , Imuno-Histoquímica , Polimorfismo de Nucleotídeo Único , Transdução de Sinais , Estados Unidos/epidemiologiaRESUMO
Edmonston vaccine strains of measles virus (MV) have shown significant antitumor activity in preclinical models of ovarian cancer. We engineered MV to express the marker peptide carcinoembryonic antigen (MV-CEA virus) to also permit real-time monitoring of viral gene expression in tumors in the clinical setting. Patients with Taxol and platinum-refractory recurrent ovarian cancer and normal CEA levels were eligible for this phase I trial. Twenty-one patients were treated with MV-CEA i.p. every 4 weeks for up to 6 cycles at seven different dose levels (10(3)-10(9) TCID(50)). We observed no dose-limiting toxicity, treatment-induced immunosuppression, development of anti-CEA antibodies, increase in anti-MV antibody titers, or virus shedding in urine or saliva. Dose-dependent CEA elevation in peritoneal fluid and serum was observed. Immunohistochemical analysis of patient tumor specimens revealed overexpression of measles receptor CD46 in 13 of 15 patients. Best objective response was dose-dependent disease stabilization in 14 of 21 patients with a median duration of 92.5 days (range, 54-277 days). Five patients had significant decreases in CA-125 levels. Median survival of patients on study was 12.15 months (range, 1.3-38.4 months), comparing favorably to an expected median survival of 6 months in this patient population. Our findings indicate that i.p. administration of MV-CEA is well tolerated and results in dose-dependent biological activity in a cohort of heavily pretreated recurrent ovarian cancer patients.
Assuntos
Antígeno Carcinoembrionário/metabolismo , Vírus do Sarampo/fisiologia , Vírus Oncolíticos/fisiologia , Neoplasias Ovarianas/terapia , Dor Abdominal/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antígeno Carcinoembrionário/genética , Chlorocebus aethiops , Fadiga/etiologia , Feminino , Febre/etiologia , Humanos , Injeções Intraperitoneais , Vírus do Sarampo/genética , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Terapia Viral Oncolítica/efeitos adversos , Terapia Viral Oncolítica/métodos , Vírus Oncolíticos/genética , Neoplasias Ovarianas/patologia , Proteínas Recombinantes de Fusão/administração & dosagem , Proteínas Recombinantes de Fusão/efeitos adversos , Resultado do Tratamento , Células VeroRESUMO
PURPOSE: Due to variation of outcome among cases, we sought to examine whether overall survival in ovarian cancer was associated with common inherited variants in 227 candidate genes from ovarian cancer-related pathways including angiogenesis, inflammation, detoxification, glycosylation, one-carbon transfer, apoptosis, cell cycle regulation, and cellular senescence. EXPERIMENTAL DESIGN: Blood samples were obtained from 325 women with invasive epithelial ovarian cancer diagnosed at the Mayo Clinic from 1999 to 2006. During a median follow-up of 3.8 years (range, 0.1-8.6 years), 157 deaths were observed. Germline DNA was analyzed at 1,416 single nucleotide polymorphisms (SNP). For all patients, and for 203 with serous subtype, we assessed the overall significance of each gene and pathway, and estimated risk of death via hazard ratios (HR) and 95% confidence intervals (CI), adjusting for known prognostic factors. RESULTS: Variation within angiogenesis was most strongly associated with survival time overall (P = 0.03) and among patients with serous cancer (P = 0.05), particularly for EIF2B5 rs4912474 (all patients HR, 0.69; 95% CI, 0.54-0.89; P = 0.004), VEGFC rs17697305 (serous subtype HR, 2.29; 95% CI, 1.34-3.92; P = 0.003), and four SNPs in VHL. Variation within the inflammation pathway was borderline significant (all patients, P = 0.09), and SNPs in CCR3, IL1B, IL18, CCL2, and ALOX5 which correlated with survival time are worthy of follow-up. CONCLUSION: An extensive multiple-pathway assessment found evidence that inherited differences may play a role in outcome of ovarian cancer patients, particularly in genes within the angiogenesis and inflammation pathways. Our work supports efforts to target such mediators for therapeutic gain.
Assuntos
Predisposição Genética para Doença , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Polimorfismo de Nucleotídeo Único , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Inflamação/genética , Pessoa de Meia-Idade , Neovascularização Patológica/genéticaRESUMO
PURPOSE: This study aimed to evaluate the safety of, immune response induced by, and efficacy of treatment with lapuleucel-T (APC8024) in patients with HER-2/neu-expressing tumors. Lapuleucel-T is an investigational active immunotherapy product consisting of autologous peripheral blood mononuclear cells, including antigen presenting cells, which are cultured ex vivo with BA7072, a recombinant fusion antigen consisting of portions of the intracellular and extracellular regions of HER-2/neu linked to granulocyte-macrophage colony-stimulating factor. EXPERIMENTAL DESIGN: Patients with metastatic breast, ovarian, or colorectal cancer whose tumors expressed HER-2 were eligible. Patients underwent leukapheresis in week 0 and received lapuleucel-T infusions in weeks 0, 2, and 4. Patients who achieved a partial response or had stable disease through week 48 were eligible for re-treatment using the same protocol and dose as their initial treatment. RESULTS: Eighteen patients were enrolled and treated. Patients showed an immune response to the immunizing antigen (BA7072) at week 8 compared with week 0 as measured by T lymphocyte proliferation and IFN-gamma enzyme-linked immunospot assay. Therapy was well tolerated. The majority (94.7%) of adverse events associated with treatment were grade 1 or 2. Two patients experienced stable disease lasting > 48 weeks. CONCLUSIONS: Autologous active cellular immunotherapy with lapuleucel-T stimulated an immune response specific to the immunizing antigen and seemed to be well tolerated. Further clinical studies to assess the clinical benefit for patients with HER/2-neu-expressing breast, ovarian, and colorectal cancer are warranted.
Assuntos
Neoplasias da Mama/terapia , Vacinas Anticâncer/imunologia , Neoplasias Colorretais/terapia , Imunoterapia , Neoplasias Ovarianas/terapia , Receptor ErbB-2/biossíntese , Adulto , Idoso , Neoplasias da Mama/imunologia , Neoplasias da Mama/secundário , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/secundário , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/secundário , Receptor ErbB-2/sangue , Receptor ErbB-2/imunologiaRESUMO
OBJECTIVE: This study assessed osteoporosis knowledge deficits among cancer patients and their spouses/partners. DESIGN: Single-institution survey (modified version of the Osteoporosis Knowledge Assessment Tool). SETTING: The Mayo Clinic in Rochester, Minnesota. PARTICIPANTS: Consecutive chemotherapy-treated cancer patients (n = 285) with their spouses/partners (n = 101). OUTCOME MEASURES: The main outcome was the percentage of cancer patients who incorrectly conveyed that 1) cancer treatment strengthens bones (or did not know) and/or 2) male cancer patients are not at risk for osteoporosis (or did not know). ANALYSES: Test scores and 95% confidence intervals (CI) as well as the correlation between patient and spouse/partner scores, are reported. RESULTS: 39% of patients (95% CI, 32% - 48%) thought cancer treatment strengthened bones or did not know, and 39% (95% CI, 32% - 48%) either answered that osteoporosis almost never occurred in men or did not know. The mean correct score on the modified Osteoporosis Knowledge Assessment Tool was 6.7 (95% CI, 6.7, 7.9), and scores from patients correlated with companion scores (r = 0.42; P < .001). CONCLUSIONS AND IMPLICATIONS: Chemotherapy-treated cancer patients and their companions have knowledge deficits concerning osteoporosis. Educational initiatives to increase awareness may be of value.
Assuntos
Conhecimentos, Atitudes e Prática em Saúde , Osteoporose/induzido quimicamente , Osteoporose/psicologia , Educação de Pacientes como Assunto , Sobreviventes/psicologia , Protocolos Antineoplásicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico por imagem , Neoplasias/tratamento farmacológico , Radiografia , Fatores de Risco , Cônjuges/educação , Cônjuges/psicologiaAssuntos
Neoplasias da Mama/patologia , Tumor Filoide/secundário , Neoplasias Cutâneas/secundário , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/cirurgia , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Tumor Filoide/tratamento farmacológico , Tumor Filoide/cirurgia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/cirurgia , Resultado do Tratamento , GencitabinaRESUMO
Ovarian carcinoma continues to be the leading cause of death among gynecologic malignancies. Paclitaxel and platinum chemotherapy is still the treatment of choice after primary debulking surgery. Salvage chemotherapy with several single agents has only modest activity and does not prolong survival of patients with relapsed ovarian carcinoma. An intense search has been made for novel approaches to treatment of ovarian cancer, and several new treatments, such as immunotherapy and gene therapy, show promise. Newer combination chemotherapy regimens and molecularly targeted therapy need to be developed. High-dose chemotherapy with autologous stem-cell transplantation appears to benefit selected groups of patients and is still investigational. Whole abdominal radiotherapy for relapsed microscopic disease should be studied in prospective randomized trials. Women with advanced ovarian carcinoma should continue to be encouraged to participate in well-designed clinical trials.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ovarianas/terapia , Terapia de Salvação , Animais , Feminino , Terapia Genética , Mobilização de Células-Tronco Hematopoéticas , Humanos , Imunoterapia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Paclitaxel/uso terapêutico , Platina/uso terapêutico , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do TratamentoRESUMO
BACKGROUND: Peripheral primitive neuroectodermal tumor (pPNET) is aggressive and rare, comprising 1% of soft tissue sarcomas. Involvement of the reproductive tract is unusual. CASE: A 35-year-old woman had a pelvic mass and omental cake. Frozen-section examination at laparotomy revealed small round cell tumor confirmed as pPNET. Chemotherapy with vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide with mesna yielded complete response. The patient's mother died of a similar tumor at age 52 years, and the patient's husband had adult Ewing sarcoma, constituting an unusual cluster of related tumors. CONCLUSIONS: Genetic recombination resulting in a chimeric transcript of the Ewing sarcoma gene and the Friend leukemia virus integration site is characteristic of these tumors. Surgical resection and multiagent chemotherapy may enhance survival.