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The goal of this study was to assess the safety of nab-paclitaxel in patients with ovarian cancer or endometrial cancer who had an allergic reaction to paclitaxel. We performed a retrospective review of patients with endometrial cancer or ovarian cancer with an allergic reaction to paclitaxel who were subsequently treated with nab-paclitaxel at the Mayo Clinic Florida from January 2016 to June 2023. A total of 43 patients with ovarian cancer (31) or endometrial cancer (12) and a paclitaxel allergic reaction were identified. All patients were pre-medicated against allergic reactions prior to paclitaxel and subsequent nab-paclitaxel. Allergic reactions to paclitaxel were mild in fourteen patients (33%), moderate in twenty-five patients (58%) and severe in four (9%) patients. None of the 43 patients had an allergic reaction to subsequent nab-paclitaxel. Our data suggests that the administration of nab-paclitaxel to endometrial cancer or ovarian cancer patients with allergic reactions to paclitaxel is safe and should be considered a preferable treatment option in this clinical situation.
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BACKGROUND: The Clinical Treatment Score post-5 years (CTS5) is a risk stratification tool used to determine the risk of late recurrence in hormone receptor-positive (HR+), HER2-negative breast cancer (BC). Limited data exist on its use in HR+, HER2-positive (HER2+) BC. PATIENTS AND METHODS: CTS5 was evaluated in HR+, HER2+ BC in the North Central Cancer Treatment Group (NCCTG) N9831 (Alliance) and NSABP B-31 (NRG) trials. RESULTS: A total of 1,862 patients with HR+, HER2+ BC without recurrence 5 years after enrollment were included. Overall, the CTS5 score was significantly associated with recurrence-free survival (RFS), with a hazard ratio (HR) of 1.35 (95% CI, 1.12-1.63; P=.002), but did not reach statistical significance in patients who received trastuzumab (n=829; HR, 1.29; 95% CI, 0.98-1.71; P=.07). CTS5 risk category was not significantly associated with RFS. In patients who received trastuzumab, other variables used in CTS5, including patient age and tumor size, were not significantly associated with RFS. N3 was significantly associated with worse outcomes (HR, 1.86; 95% CI, 1.09-3.17; P=.02) compared with N0-N1. Paradoxically, higher tumor grade was associated with better outcomes after 5 years in the multivariate analysis (HR, 0.71; 95% CI, 0.50-1.00; P=.05). The incidence of recurrences or deaths between years 5 to 10 was 10.6% in the CTS5 low-risk category, 5.6% in the intermediate-risk category, and 9.8% in the high-risk category. CONCLUSIONS: The CTS5 model does not accurately predict the risk of late recurrence in HR+, HER2+ BC treated with adjuvant trastuzumab in the N9831 and B-31 trials. This study underlines the need to develop a new prognostic model to better delineate the risk of late recurrence in patients with HR+, HER2+ BC receiving adjuvant trastuzumab. CLINICALTRIALS: gov identifiers: NCT00005970 (NCCTG N9831) and NCT00004067 (NRG/NSABP B-31).
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Neoplasias da Mama , Recidiva Local de Neoplasia , Receptor ErbB-2 , Receptores de Progesterona , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/metabolismo , Feminino , Receptor ErbB-2/metabolismo , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/epidemiologia , Idoso , Adulto , Receptores de Progesterona/metabolismo , Receptores de Estrogênio/metabolismo , Medição de Risco/métodos , Prognóstico , Trastuzumab/uso terapêutico , Biomarcadores Tumorais/metabolismo , Fatores de RiscoRESUMO
Background: Human Papillomavirus (HPV) vaccination rates remain low in the U.S., particularly among minorities and low-income, uninsured patients. We report preliminary data on a pilot study program providing education and free HPV vaccination at a clinic serving low-income uninsured adults. Methods: From October 2020 through October 2022, we assessed HPV vaccination knowledge, awareness, and prevalence of hesitancy towards receiving the vaccine among low-income uninsured patients age 18-45. The Parents Attitudes about Childhood Vaccines (PACV) survey was modified and used to evaluate vaccine hesitancy. An educational video on HPV was shown to patients declining vaccination. Results: 43 patients were enrolled. 69.8% had heard of the HPV vaccine and 85.7% were non-hesitant based on PACV scores of 0-49. Black participants had a statistically significant higher PACV score (more hesitant) than White participants. Familiarity with the HPV vaccine correlated with lower PACV scores. Only 27% completed all three HPV vaccine doses. Discussion: The availability of an education program together with free HPV vaccination are not sufficient to achieve adequate vaccination rates in low-income, uninsured adults. Innovative, culturally sensitive education and supportive interventions, in addition to access to free HPV vaccination, are warranted in order to improve vaccination rates in this underserved population.
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BACKGROUND: Clinical trials are an essential part of advancing care for cancer patients. Historically, however, racial minorities and females have been underrepresented in these trials. Efforts like the National Institute of Health Revitalization Act attempted to mitigate these disparities, but despite these efforts, they continue to exist. These disparities can subsequently lead to minorities and females receiving suboptimal care. AIMS: The purpose of our study was to understand the changing trends in reporting of participant race and sex as a demographic variable in phase III lung cancer clinical trials published over the last 35 years given these consequences of poor representation. METHODS AND RESULTS: A total of 426 articles reporting the results of phase III lung cancer clinical trials published from 1984 to 2019 were identified in PubMed. From these articles, data on participant sex and race were collected from the demographic tables to construct the database for this study. This database was subsequently used to determine the rate of reporting of demographic factors like race and sex and the participation trends over the time of minority and female participation in lung cancer phase III clinical trials. The SciPy Stats package for Python was used to calculate descriptive statistics, 95% confidence intervals, two sample t-test, one-way analysis of variance test, and Pearson's correlation coefficients. The Matplotlib package for Python was used for figure generation. Only 137 (32.2%) of the 426 studies analyzed reported the race of participants. Among those studies, we found that the mean participation rate of White participants was significantly higher (82.65%; p < .001). We found a decrease in African American participants and an increase in Asian participants over time. When looking at sex, we found that although the rate of male participation (69.02%) was significantly higher than that of female participation (30.98%), female participation has improved with time at a rate of 0.65% per year. CONCLUSION: We found that the reporting and participation of minority races continue to lag that of other demographic factors like sex in phase III clinical trials in lung cancer. Based on our analysis, we note a decline in participation of African Americans in lung cancer phase III clinical trials despite the rising incidence of lung cancer.
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Pesquisa Biomédica , Neoplasias Pulmonares , Feminino , Humanos , Masculino , Negro ou Afro-Americano , Neoplasias Pulmonares/epidemiologia , Neoplasias Pulmonares/etnologia , Neoplasias Pulmonares/terapia , Grupos Minoritários , Aceitação pelo Paciente de Cuidados de Saúde , Fatores SexuaisRESUMO
Background: The cardiotoxic effects of doxorubicin, trastuzumab, and other anticancer agents are well known, but molecular genetic testing is lacking for the early identification of patients at risk for therapy-related cardiac toxicity. Methods: Using the Agena Bioscience MassARRAY system, we genotyped TRPC6 rs77679196, BRINP1 rs62568637, LDB2 rs55756123, RAB22A rs707557, intergenic rs4305714, LINC01060 rs7698718, and CBR3 rs1056892 (V244M) (previously associated with either doxorubicin or trastuzumab-related cardiotoxicity in the NCCTG N9831 trial of anthracycline-based chemotherapy ± trastuzumab) in 993 patients with HER2+ early breast cancer from the NSABP B-31 trial of adjuvant anthracycline-based chemotherapy ± trastuzumab. Association analyses were performed with outcomes of congestive heart failure (N = 29) and maximum decline in left ventricular ejection fraction (LVEF) using logistic and linear regression models, respectively, under an additive model with age, baseline LVEF, and previous use of hypertensive medications as covariates. Results: Associations of maximum decline in LVEF in the NCCTG N9831 patients did not replicate in the NSABP B-31 patients. However, TRPC6 rs77679196 and CBR3 rs1056892 were significantly associated with congestive heart failure, p < 0.05, with stronger associations observed in patients treated with chemotherapy only (no trastuzumab) or in the combined analysis of all patients relative to those patients treated with chemotherapy + trastuzumab. Conclusions: TRPC6 rs77679196 and CBR3 rs1056892 (V244M) are associated with doxorubicin-induced cardiac events in both NCCTG N9831 and NSABP B-31. Other variants previously associated with trastuzumab-related decline in LVEF failed to replicate between these studies.
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BACKGROUND: The objective of this study was to evaluate the efficacy of gemcitabine plus nab-paclitaxel in patients with recurrent ovarian cancer. METHODS: We performed a single institution retrospective review of patients with recurrent ovarian cancer who were treated with gemcitabine plus nab-paclitaxel from 2012 to 2018 at the Mayo Clinic in Florida. RESULTS: Twenty patients were identified and the median PFS for patients treated with gemcitabine plus nab-paclitaxel was 9 months (95% CI, 5.7-20.7). Overall, 17 of the 20 patients (85%) achieved a clinical benefit (complete response 5%, partial response 55%, or stable disease at 3 months 25%). For platinum-sensitive disease and platinum-resistant disease, the median OS were 38.7 months (95% CI, 5.8-63.1) and 31.2 months (95% CI, 12.8-51.8), respectively (p = 0.4306). CONCLUSION: This well-tolerated regimen shows promising activity in recurrent ovarian cancer and is a viable option for patients who are intolerant to paclitaxel or carboplatin because of allergic reactions.
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Nanopartículas , Neoplasias Ovarianas , Humanos , Feminino , Gencitabina , Paclitaxel Ligado a Albumina/efeitos adversos , Estudos Retrospectivos , Desoxicitidina/uso terapêutico , Resultado do Tratamento , Paclitaxel/efeitos adversos , Albuminas/uso terapêutico , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/etiologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
â¢Immune checkpoint inhibitors can be safely administered to patients with dermatomyositis.â¢Immunosuppressants did not impact the efficacy of treatment with an immune check point inhibitor.â¢Patients with autoimmune disorders who require immune check point inhibitors should be monitored by a rheumatologist.
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Trastuzumab acts in part through the adaptive immune system. Previous studies showed that enrichment of immune-related gene expression was associated with improved outcomes in HER2-positive (HER2+) breast cancer. However, the role of the immune system in response to lapatinib is not fully understood. Gene expression analysis was performed in 1,268 samples from the North Central Cancer Treatment Group (NCCTG) N9831 and 244 samples from the NeoALTTO trial. In N9831, enrichment of CD45 and immune-subset signatures were significantly associated with improved outcomes. We identified a novel 17-gene adaptive immune signature (AIS), which was found to be significantly associated with improved RFS among patients who received adjuvant trastuzumab (HR 0.66, 95% CI 0.49-0.90, Cox regression model p = 0.01) but not in patients who received chemotherapy alone (HR 0.96, 95% CI 0.67-1.40, Cox regression model p = 0.97). This result was validated in NeoALTTO. Overall, AIS-low patients had a significantly lower pathologic complete response (pCR) rate compared with AIS-high patients (χ2 p < 0.0001). Among patients who received trastuzumab alone, pCR was observed in 41.7% of AIS-high patients compared with 9.8% in AIS-low patients (OR of 6.61, 95% CI 2.09-25.59, logistic regression model p = 0.003). More importantly, AIS-low patients had a higher pCR rate with an addition of lapatinib (51.1% vs. 9.8%, OR 9.65, 95% CI 3.24-36.09, logistic regression model p < 0.001). AIS-low patients had poor outcomes, despite receiving adjuvant trastuzumab. However, these patients appear to benefit from an addition of lapatinib. Further studies are needed to validate the significance of this signature to identify patients who are more likely to benefit from dual anti-HER2 therapy. ClinicalTrials.gov Identifiers: NCT00005970 (NCCTG N9831) and NCT00553358 (NeoALTTO).
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OBJECTIVE: We describe a phase II clinical trial of the combination of ribociclib and letrozole for treatment of relapsed oestrogen receptor (ER)-positive ovarian cancer (OC) and endometrial cancer (EC). The primary endpoint was the proportion of patients alive, progression-free survival (PFS), and still on treatment at 12 weeks (PFS12), with 45% or greater considered positive. METHODS: Patients with measurable, relapsed ER-positive OC or EC (platinum-sensitive or resistant) were eligible and treated with 400 mg of oral ribociclib and 2.5 mg of oral letrozole daily. Patient-derived xenografts (PDXs) were created from imaging-guided tumour biopsies. RESULTS: Forty patients (20 OC and 20 EC) were enrolled. A PFS12 of 55% was observed in the EC cohort and 50% in the OC cohort. A PFS greater or equal to 24 weeks (PFS24) was seen in 20% (4/20) of the OC cohort and 35% (7/20) of the EC cohort. The greatest benefit was seen in low-grade serous OC (LGSOC) (3/3, 100% PFS24) and grades 1 and 2 EC (5/11, 45% PFS24). All three LGSOC patients obtained at least a partial response lasting for over 2 years, with two of the three patients still on treatment. PDX tumour engraftment was feasible in 45% of patients. Positive survival effects of the combination of ribociclib and letrozole were observed in two of three EC PDX models. CONCLUSION: Ribociclib and letrozole have promising clinical activity in relapsed ER-positive OC and EC, particularly in LGSOC and relapsed ER-positive grade 1 and 2 EC. Generation of PDX models is feasible with positive survival effects observed in EC models. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov registry (NCT02657928).
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Neoplasias do Endométrio , Receptores de Estrogênio , Aminopiridinas , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Intervalo Livre de Doença , Neoplasias do Endométrio/tratamento farmacológico , Feminino , Humanos , Letrozol/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Purinas , Receptores de Estrogênio/uso terapêuticoRESUMO
BACKGROUND: The biology of some hematological diseases varies among different populations. No previous studies have evaluated the clinical behavior of mantle cell lymphoma (MCL) in México. OBJECTIVE AND METHODS: This is a retrospective review of MCL cases seen in Mexico from January 2003 to June 2020. A total of 12 cases were identified. RESULTS: There were nine males and three females; median age was 56 years. Eight patients had a high MCL international prognostic index score, one was intermediate, and three were low. Five patients had circulating malignant monoclonal cells. Initial treatment included rituximab, cyclophosphamide, daunorubicin, vincristine, and prednisone (R-CHOP) and CHOP. Subsequent treatment included hematopoietic stem cell transplantation in five patients; two were given maintenance therapy. Splenectomy was done in four patients. Median overall survival (OS) for all the patients has not been reached and exceeds 162 mos: OS at 162 mos was 56%. Achieving a complete remission (CR) after the first treatment was a significant prognostic factor, with a median OS exceeding 141 mos in patients achieving CR, and 16 mos among those not achieving CR (p = 0.0006). CONCLUSION: Some of MCL patients in Mexico have an indolent clinical course, particularly patients who achieve a CR to initial treatment and who undergo splenectomy.
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BACKGROUND: There are few treatment options for patients with leptomeningeal metastases (LM). METHODS: We report a case series of patients with breast cancer and LM treated with intra-CSF topotecan (TOPO). Outcome was assessed by clinical exam and MRI at baseline, at end of induction (4-5 weeks), then every 3 months; CSF cytology was determined at baseline and with each treatment. RESULTS: Thirty-one women [median age, 58 (37-81); median KPS 60 (40-100)] received treatment. At baseline, 68% had positive CSF cytology, and 90%, leptomeningeal enhancement on MRI. 84% of patients also received focal RT (not during TOPO) and 77% received concomitant systemic hormonal or chemotherapy. Median number of TOPO treatments was 14.5 (range, 3-71); median duration of treatment, 11 weeks (1-176); and median OS, 6.9 months (range, 0.9-48.8). Patients remaining progression-free during 4-6 weeks of induction (81%) had a median OS of 11.5 months (range, 1.8-48.8). Overall neurologic PFS at 6, 12, and 24 months was 39%, 26%, and 6%, respectively. Clearing of CSF malignant cells for >3 consecutive samples occurred in 10/21 (48%) patients with positive CSF cytology at baseline, remaining clear for a median duration of 15.9 months (range, 1.4-34.5). Grade 3 adverse events included headache or vomiting (3pts), T2 hyperintensity surrounding the ventricular catheter (2 pts), and meningitis (2 pts). CONCLUSIONS: Intra-CSF TOPO, with focal RT as needed for symptomatic areas of enhancement produced durable clearing of CSF malignant cells in 48% of patients positive at baseline, with promising median PFS and OS.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias Meníngeas/tratamento farmacológico , Inibidores da Topoisomerase I/administração & dosagem , Topotecan/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/líquido cefalorraquidiano , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Feminino , Humanos , Infusões Intraventriculares , Imageamento por Ressonância Magnética , Masculino , Neoplasias Meníngeas/líquido cefalorraquidiano , Neoplasias Meníngeas/diagnóstico por imagem , Neoplasias Meníngeas/secundário , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Radioterapia Adjuvante , Estudos Retrospectivos , Fatores de Tempo , Inibidores da Topoisomerase I/efeitos adversos , Topotecan/efeitos adversosRESUMO
PURPOSE: To investigate whether there are differences in diversity, taxonomic composition, and predicted functional pathways of the gut microbiome between Island Hispanic Puerto Ricans (HPR) and mainland non-Hispanic whites (NHW) measured before and at the end of chemo-radiation (CRT) for Rectal Cancer. METHODS: Fifty-six stool samples of newly diagnosed rectal cancer patients (25 HPR and 31 NHW) were amplicon-sequenced during chemo-radiotherapy. 16S rRNA gene data was analyzed using QIIME2, phyloseq, and LEfSe. RESULTS: We observed similar within-sample alpha diversity for HPR and NHW participants during CRT. However, at the end of CRT, several taxa were present at significantly different abundances across both groups. Taxa enriched in the gut of HPR compared to NHW included Muribaculaceae, Prevotella 2 and 7, Gemella, Bacillales Family XI, Catenibacterium, Sutterella, Pasteurellales, and Pasteurellaceae genera, whereas over-represented taxa in NHW participants were Turicibacter and Eubacteriaceae. Significant differences in predicted HPR microbiota functions included pathways for synthesis of L-methionine and degradation of phenylethylamine and phenylacetate. CONCLUSION: In this pilot study, taxonomic analyses and functional predictions of the gut microbiomes suggest greater inflammatory potential in gut microbial functions among HPR rectal cancer patients undergoing CRT compared to that of NHW participants.
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Quimiorradioterapia/métodos , Microbioma Gastrointestinal , Hispânico ou Latino/estatística & dados numéricos , Neoplasias Retais/microbiologia , População Branca/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Projetos Piloto , Prognóstico , Porto Rico/epidemiologia , Neoplasias Retais/epidemiologia , Neoplasias Retais/terapia , Estados Unidos/epidemiologiaRESUMO
BACKGROUND/OBJECTIVES: Interplay between the Hedgehog (HH) and epidermal growth factor receptor (EGFR) pathways modulating the outcome of their signaling activity have been reported in various cancers including pancreatic ductal adenocarcinoma (PDAC). Therefore, simultaneous targeting of these pathways may be clinically beneficial. This Phase I study combined HH and EGFR inhibition in metastatic PDAC patients. METHODS: Combined effects of HH and EGFR inhibition using Vismodegib and Erlotinib with or without gemcitabine in metastatic solid tumors were assessed by CT. Another cohort of patients with metastatic PDAC was evaluated by FDG-PET and tumor biopsies-derived biomarkers. RESULTS: Treatment was well tolerated with the maximum tolerated dose cohort experiencing no grade 4 toxicities though 25% experienced grade 3 adverse effects. Recommended phase II dose of Vismodegib and Erlotinib were each 150 mg daily. No tumor responses were observed although 16 patients achieved stable disease for 2-7 cycles. Paired biopsy analysis before and after first cycle of therapy in PDAC patients showed reduced GLI1 mRNA, phospho-GLI1 and associated HH target genes in all cases. However, only half of the cases showed reduced levels of desmoplasia or changes in fibroblast markers. Most patients had decreased phospho-EGFR levels. CONCLUSIONS: Vismodegib and Erlotinib combination was well-tolerated although overall outcome in patients with metastatic PDAC was not significantly impacted by combination treatment. Biomarker analysis suggests direct targets inhibition without significantly affecting the stromal compartment. These findings conflict with pre-clinical mouse models, and thus warrant further investigation into how upstream inhibition of these pathways is circumvented in PDAC.
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Anilidas/uso terapêutico , Antineoplásicos/uso terapêutico , Cloridrato de Erlotinib/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Piridinas/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: Recent trials have shown potential benefit of extended adjuvant endocrine therapy and relatively high risk of recurrence (RoR) after 5 years in hormone receptor-positive (HR+) human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Although risk of late relapse in HR+ HER2- breast cancer is fairly well defined, the risk in HER2-positive (HER2+) breast cancer treated with adjuvant trastuzumab-based chemotherapy remains largely unknown. METHODS: We included 3,177 patients with HER2+ breast cancer treated with adjuvant chemotherapy alone or with trastuzumab from the North Central Cancer Treatment Group N9831 (ClinicalTrials.gov identifier: NCT00005970) and National Surgical Adjuvant Breast and Bowel Project B-31 (ClinicalTrials.gov identifier: NCT00004067) trials. RESULTS: Overall, HR+ breast cancer was significantly associated with improved recurrence-free survival (RFS) during the first 5 years (hazard ratio, 0.65; 95% CI, 0.56 to 0.77; P < .001). Among patients treated with trastuzumab, cumulative hazard for RFS was lower in patients with HR+ HER2+ breast cancer during the first 5 years (10.96% v 17.48%; hazard ratio, 0.60; 95% CI, 0.45 to 0.79; P < .001). However, there was no significant difference in RFS based on HR status during years 5 to 10 (hazard ratio, 1.32; 95% CI, 0.93 to 1.88; P = .12). A comparable degree of trastuzumab benefit was observed in HR+ and HR- breast cancers ( P for interaction = .87). Furthermore, we observed low RoR in years 5 to 10 among patients with HR+ HER2+ breast cancer: 3.23% in patients without lymph node involvement (N0) and 6.39% in patients with involvement of one to three lymph nodes (N1). CONCLUSION: The benefit of adjuvant trastuzumab persists for a long time. A distinct pattern of recurrence was observed between HR+ and HR- HER2+ disease but with similar degree of benefit from adjuvant trastuzumab. RoR in years 5 to 10 in HR+ HER2+ breast cancer is low, particularly in patients with N0 or N1 disease.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/epidemiologia , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Seguimentos , Humanos , Incidência , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/diagnóstico , Paclitaxel/administração & dosagem , Prognóstico , Taxa de Sobrevida , Trastuzumab/administração & dosagem , Estados Unidos/epidemiologia , Adulto JovemRESUMO
IMPORTANCE: Patients with recurrent ovarian carcinoma frequently develop resistance to platinum-based chemotherapy, at which time treatment options become limited. OBJECTIVE: To evaluate the poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor niraparib combined with pembrolizumab in patients with recurrent ovarian carcinoma. DESIGN, SETTING, AND PARTICIPANTS: The TOPACIO/KEYNOTE-162 (Niraparib in Combination With Pembrolizumab in Patients With Triple-Negative Breast Cancer or Ovarian Cancer) trial, an open-label, single-arm phases 1 and 2 study enrolled women with advanced or metastatic triple-negative breast cancer (TNBC) or recurrent ovarian carcinoma, irrespective of BRCA mutation status. Median follow-up was 12.4 months (range, 1.2 to ≥23.0 months). Data were collected from April 15, 2016, through September 4, 2018, with September 4, 2018, as a data cutoff, and analyzed from September 4, 2018, through January 30, 2019. INTERVENTIONS: The recommended phase 2 dose (RP2D) was 200 mg of oral niraparib once daily and 200 mg of intravenous pembrolizumab on day 1 of each 21-day cycle. MAIN OUTCOMES AND MEASURES: The primary objectives of phase 1 were to evaluate dose-limiting toxic effects and establish the RP2D and dosing schedule. The primary objective of phase 2 was to assess objective response rate (ORR; complete plus partial responses). Results from the phase 1 ovarian carcinoma and TNBC cohorts and phase 2 ovarian carcinoma cohort are reported. Because of the similarity in the phase 1 and 2 ovarian carcinoma populations, the data were pooled to perform an integrated efficacy analysis. RESULTS: Fourteen patients (9 with ovarian carcinoma and 5 with TNBC) in phase 1 and 53 patients with ovarian carcinoma in phase 2 were enrolled, for a pooled ovarian carcinoma cohort of 62 patients (median age, 60 years [range, 46-83 years]). In the integrated efficacy phases 1 and 2 ovarian carcinoma population (60 of 62 evaluable patients), ORR was 18% (90% CI, 11%-29%), with a disease control rate of 65% (90% CI, 54%-75%), including 3 (5%) with confirmed complete responses, 8 (13%) with confirmed partial responses, 28 (47%) with stable disease, and 20 (33%) with progressive disease. The ORRs were consistent across subgroups based on platinum-based chemotherapy sensitivity, previous bevacizumab treatment, or tumor BRCA or homologous recombination deficiency (HRD) biomarker status. Median duration of response was not reached (range, 4.2 to ≥14.5 months). At data cutoff, 2 patients with a response and 1 patient with stable disease continued to receive treatment. CONCLUSIONS AND RELEVANCE: Niraparib in combination with pembrolizumab is tolerable, with promising antitumor activity for patients with ovarian carcinoma who have limited treatment options regardless of platinum status, biomarker status, or prior treatment with bevacizumab. Responses in patients without tumor BRCA mutations or non-HRD cancers were higher than expected with either agent as monotherapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02657889.
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OBJECTIVE: Endocrine therapy is often considered as a treatment for hormone-responsive gynecologic malignancies. In breast cancer, activating mutations in the estrogen receptor (mutESR1) contribute to therapeutic resistance to endocrine therapy, especially aromatase inhibitors (AIs). The purpose of this study was to evaluate the frequency and clinical relevance of ESR1 genomic alterations in gynecologic malignancies. METHODS: DNA from FFPE tumor tissue obtained during routine clinical care for 9645 gynecologic malignancies (ovary, fallopian tube, uterus, cervix, vagina, vulvar, and placenta) was analyzed for all classes of genomic alterations (base substitutions (muts), insertions, deletions, rearrangements, and amplifications) in ESR1 by hybrid capture next generation sequencing. A subset of alterations was characterized in laboratory-based transcription assays for response to endocrine therapies. RESULTS: A total of 295 ESR1 genomic alterations were identified in 285 (3.0%) cases. mutESR1 were present in 86 (0.9%) cases and were more common in uterine compared to other cancers (2.0% vs <1%, respectively pâ¯<â¯0.001). mutESR1 were enriched in carcinomas with endometrioid versus serous histology (4.4% vs 0.2% respectively, pâ¯<â¯0.0001 in uterine and 3.5% vs 0.3% respectively, pâ¯=â¯0.0004 in ovarian carcinomas). In three of four patients with serial sampling, mutESR1 emerged under the selective pressure of AI therapy. Despite decreased potency of estrogen receptor (ER) antagonists in transcriptional assays, clinical benefit was observed following treatment with selective ER-targeted therapy, in one case lasting >48â¯months. CONCLUSIONS: While the prevalence of ESR1 mutations in gynecologic malignancies is low, there are significant clinical implications useful in guiding therapeutic approaches for these cancers.
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Inibidores da Aromatase/administração & dosagem , Receptor alfa de Estrogênio/genética , Neoplasias dos Genitais Femininos/tratamento farmacológico , Neoplasias dos Genitais Femininos/genética , Moduladores Seletivos de Receptor Estrogênico/administração & dosagem , Adulto , Inibidores da Aromatase/farmacologia , DNA de Neoplasias/genética , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Mutação , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Transcrição Gênica/efeitos dos fármacos , Transcriptoma , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: Young age has been shown to be an independent predictor of poor outcome in breast cancer. In HER2-positive breast cancer, the effects of aging remain largely unknown. EXPERIMENTAL DESIGN: A total of 4,547 patients were included [3,132 from North Central Cancer Treatment Group (NCCTG) N9831 and 1,415 from National Surgical Adjuvant Breast and Bowel Project (NSABP) B-31]. Pathologic stromal tumor-infiltrating lymphocyte (sTIL) and molecular tumor infiltrating lymphocyte (mTIL) signatures were evaluated. RESULTS: In NCCTG N9831, comparable benefit of trastuzumab was observed in all patients [age ≤ 40; HR, 0.43; 95% confidence interval (CI), 0.28-0.66; P < 0.001; and age > 40; HR, 0.56; 95% CI, 0.45-0.69; P < 0.001]. Similar results were observed in NSABP B-31 (age ≤ 40; HR, 0.45; 95% CI, 0.29-0.68; P < 0.001; and age > 40; HR, 0.42; 95% CI, 0.33-0.54; P < 0.001). Among patients who received chemotherapy alone, younger age was associated with poor outcome in the hormone receptor-positive subset, but not the hormone receptor-negative subset, in both trials. Although there was no association between sTILs and age, a small, but significant increase in mTIL CD45 and some immune subset signatures were observed. Among patients who received chemotherapy alone, patients over 40 years of age with lymphocyte-predominant breast cancer had excellent outcome, with 95% remaining recurrence free at 15 years. CONCLUSIONS: Among patients treated with trastuzumab, there was no significant difference in outcome related to age. Our study suggests that trastuzumab can negate the poor prognosis associated with young age.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Recidiva Local de Neoplasia/mortalidade , Receptor ErbB-2/metabolismo , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/imunologia , Recidiva Local de Neoplasia/patologia , Paclitaxel/administração & dosagem , Taxa de Sobrevida , Trastuzumab/administração & dosagem , Adulto JovemRESUMO
OBJECTIVE: The established link between oestrogen and breast cancer occurs via both oestrogen receptor (ER)-mediated and non ER-mediated mechanisms. The term genotoxic estrogens describes mutagenic metabolites, including oestrogen catechols and quinones, which have been linked to breast carcinogenesis in post-menopausal women. We aimed to assess whether the route of administration of 17ß oestradiol (E2 ) affects the accumulation of genotoxic oestrogen metabolites in a model of ovarian failure in young girls with Turner syndrome. METHODS: Stored plasma samples obtained at 0 and 12 months were used from 40 adolescents with Turner syndrome who participated in a 12 months randomized controlled trial of the metabolic impact of E2 orally (2 mg/d) vs transdermally (100 µg/d); dose escalation allowed matching of unconjugated E2 levels in the parent study. We measured 12 oestrogen metabolites (total concentrations = conjugated and unconjugated) using a highly sensitive LCMSMS assay. Results from 48 normally menstruating adolescents were used for comparison. RESULTS: After treatment, least square mean (SE) total E2 concentrations were higher in the oral vs transdermal group (6784 pmol/L vs 1123 [1614], P < 0.0001), as was oestrone (E1 ) (91 060 pmol/L vs 19 278 [16 534], P < 0.0001). Also, higher after oral treatment were catechol-oestrogens 4-hydroxy-E2 (149 vs 28 [±49] pmol/L), 2-hydroxy-E2 (300 vs 76 [±52]), 4-hydroxy-E1 (450 vs 105 [±113]), 2-hydroxy-E1 (3094 vs 740 [±684]) and 16α-hydroxy-E1 (3,007 vs 157 [±534]) (<0.001 between groups). Levels were much closer to controls in the transdermal group. CONCLUSIONS: Common feminizing doses of oral oestradiol for 12 months result in substantial accumulation of unphysiologic, genotoxic oestrogens compared to transdermal oestradiol, expanding concerns about oral oestrogens' first hepatic passage. Further studies assessing long-term risks of these metabolites in women taking different forms of oestrogen are needed.
Assuntos
Estrogênios/administração & dosagem , Síndrome de Turner/tratamento farmacológico , Administração Cutânea , Administração Oral , Adolescente , Cromatografia Líquida , Estradiol/administração & dosagem , Estradiol/sangue , Estradiol/metabolismo , Estradiol/toxicidade , Estrogênios/sangue , Estrogênios/metabolismo , Estrogênios/toxicidade , Feminino , Humanos , Dose Máxima Tolerável , Mutagênicos/análise , Espectrometria de Massas em Tandem , Resultado do TratamentoRESUMO
OBJECTIVE/BACKGROUND: The quality of life (QOL) of hematopoietic stem cell transplant (HSCT) patients and their caregivers decreases during the first 8â¯days after HSCT. METHODS: This prospective pilot study collected preliminary data on the impact of posttransplant living arrangements (hospital hospitality house [HHH] vs. hotel, apartment, or house ["hotel"]) and other factors on the QOL of HSCT patients and their caregivers. The predefined primary end point was QOL of patients and their caregivers on Day 30 (QOL30) as measured by the linear analog self-assessment (LASA). RESULTS: Forty-four HSCT patients participated (HHH 23, hotel 21; allogeneic 18, autologous 26). No significant differences in QOL30 (mean LASA score) were noted between patient groups (55.6 [HHH] vs. 72.2 [hotel], pâ¯=â¯.06) or between caregiver groups (77.8 [HHH] vs. 88.9 [hotel], pâ¯=â¯.20). Multivariate analysis for QOL30 showed that baseline QOL (pâ¯=â¯.006) and age (pâ¯=â¯.049) were significant predictors of QOL30 after adjustment for sex, post-HSCT living place, and transplant type. Older patients (≥60â¯years) had a significantly lower QOL30 than younger patients (mean score, 51.6 vs. 75.3; pâ¯=â¯.02). CONCLUSION: Efforts to improve QOL30 of HSCT patients and caregivers in the confined environment of an HHH should focus on patients with low baseline QOL and older patients.