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1.
N Engl J Med ; 384(16): 1529-1541, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33882206

RESUMO

BACKGROUND: Patients with metastatic triple-negative breast cancer have a poor prognosis. Sacituzumab govitecan is an antibody-drug conjugate composed of an antibody targeting the human trophoblast cell-surface antigen 2 (Trop-2), which is expressed in the majority of breast cancers, coupled to SN-38 (topoisomerase I inhibitor) through a proprietary hydrolyzable linker. METHODS: In this randomized, phase 3 trial, we evaluated sacituzumab govitecan as compared with single-agent chemotherapy of the physician's choice (eribulin, vinorelbine, capecitabine, or gemcitabine) in patients with relapsed or refractory metastatic triple-negative breast cancer. The primary end point was progression-free survival (as determined by blinded independent central review) among patients without brain metastases. RESULTS: A total of 468 patients without brain metastases were randomly assigned to receive sacituzumab govitecan (235 patients) or chemotherapy (233 patients). The median age was 54 years; all the patients had previous use of taxanes. The median progression-free survival was 5.6 months (95% confidence interval [CI], 4.3 to 6.3; 166 events) with sacituzumab govitecan and 1.7 months (95% CI, 1.5 to 2.6; 150 events) with chemotherapy (hazard ratio for disease progression or death, 0.41; 95% CI, 0.32 to 0.52; P<0.001). The median overall survival was 12.1 months (95% CI, 10.7 to 14.0) with sacituzumab govitecan and 6.7 months (95% CI, 5.8 to 7.7) with chemotherapy (hazard ratio for death, 0.48; 95% CI, 0.38 to 0.59; P<0.001). The percentage of patients with an objective response was 35% with sacituzumab govitecan and 5% with chemotherapy. The incidences of key treatment-related adverse events of grade 3 or higher were neutropenia (51% with sacituzumab govitecan and 33% with chemotherapy), leukopenia (10% and 5%), diarrhea (10% and <1%), anemia (8% and 5%), and febrile neutropenia (6% and 2%). There were three deaths owing to adverse events in each group; no deaths were considered to be related to sacituzumab govitecan treatment. CONCLUSIONS: Progression-free and overall survival were significantly longer with sacituzumab govitecan than with single-agent chemotherapy among patients with metastatic triple-negative breast cancer. Myelosuppression and diarrhea were more frequent with sacituzumab govitecan. (Funded by Immunomedics; ASCENT ClinicalTrials.gov number, NCT02574455; EudraCT number, 2017-003019-21.).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Camptotecina/análogos & derivados , Moléculas de Adesão Celular/antagonistas & inibidores , Imunoconjugados/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígenos de Neoplasias , Antineoplásicos/efeitos adversos , Camptotecina/efeitos adversos , Camptotecina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoconjugados/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Intervalo Livre de Progressão , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/mortalidade , Carga Tumoral
2.
Brain Behav Immun ; 107: 124-131, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36208853

RESUMO

BACKGROUND: Inflammation can have social consequences, which may be relevant to inflammation's link with depression. The current study tests whether a typhoid vaccine increases feelings of social disconnection and avoidance behavior. METHOD: In two full-day visits at least three weeks apart, 172 postmenopausal breast cancer survivors (Stage I-IIIA) each received a typhoid capsular polysaccharide vaccination and a saline placebo injection in a random sequence. Blood was drawn prior to the injection, as well as every 90 min thereafter for 8 h to assess the inflammatory response (interleukin-6, IL-6; interleukin-1 receptor antagonist, IL-1Ra). At both visits, women completed the Social Connection Scale at 0 and 8.5 h post-vaccination as well as implicit and explicit social avoidance tasks at 7 h post-vaccination. RESULTS: The typhoid vaccine triggered rises in both inflammatory markers (ps < 0.01), but it did not impact feelings of social connection (p = .32), or performance on the implicit (p = .34) or explicit tasks (p = .37). Inflammatory rises did not predict feelings of social connection (ps > 0.64) or performance on explicit (ps > 0.73) or implicit (ps > 0.88) social avoidance tasks. CONCLUSION: Milder inflammatory stimuli may not affect social processes. Higher levels of inflammation or, relatedly, more sickness symptoms may be necessary to recapitulate prior findings of social avoidance.


Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Vacinas Tíficas-Paratíficas , Feminino , Humanos , Pessoa de Meia-Idade , Comportamento Social
3.
Ann Behav Med ; 57(10): 888-898, 2023 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-37335884

RESUMO

BACKGROUND: Breast cancer survivors often experience many somatic and cognitive side effects resulting from their cancer diagnosis and treatment, including higher rates of pain, fatigue, and memory/concentration problems. Emotion regulation offers opportunities to either enhance or dampen physical health. PURPOSE: In a secondary analysis of a double-blind randomized controlled trial (RCT) using a typhoid vaccine to assess factors associated with breast cancer survivors' inflammatory responses, we assessed how two specific aspects of emotion regulation, mindfulness, and worry, corresponded to acute changes in focus problems, memory problems, and fatigue along with performance on pain sensitivity and cognitive tasks across two visits among breast cancer survivors. METHODS: Breast cancer survivors (N = 149) completed two 8.5-hr visits at a clinical research center. Survivors were randomized to either the vaccine/saline placebo or a placebo/vaccine sequence. Worry and mindfulness questionnaires provided data on trait-level emotion regulation abilities. Fatigue, memory problems, and focus difficulties were assessed via Likert scales six times-once before the injections and then every 90 min for 7.5 hr thereafter. Women also completed a pain sensitivity task and several cognitive tasks at each visit. RESULTS: Findings from this study showed that breast cancer survivors who worried more and were less mindful experienced subjective memory problems, focus problems, and cold pain sensitivity across two visits and irrespective of injection type. Lower mindfulness also corresponded to higher subjective fatigue and hot pain sensitivity and objective ratings. Emotion regulation skills did not predict objective pain sensitivity or cognitive problems. CONCLUSION: Results from this study highlight the benefits of adaptive emotion regulation in helping mitigate symptoms associated with breast cancer survivorship.


Breast cancer survivors experience side effects resulting from their cancer diagnosis and treatment, including higher rates of pain, fatigue, and memory/concentration problems. Emotion regulation offers the possibility to either better or worse physical health. This study assessed how two emotion regulation strategies, mindfulness and worry, corresponded to changes in focus problems, memory problems, and fatigue along with performance on pain sensitivity and cognitive tasks across two visits among breast cancer survivors. A total of 149 survivors completed 2 day-long visits in the laboratory where they rated their fatigue and memory problems six times across the day, completed cognitive tests, and a pain sensitivity test. Findings from this study showed that breast cancer survivors who worried more and were less mindful experienced subjective memory problems, focus problems, and cold pain sensitivity across two visits. Emotion regulation skills did not predict objective pain sensitivity or cognitive problems. Results from this study highlight the benefits of adaptive emotion regulation skills like mindfulness in helping improve the cognitive and physical symptoms commonly experienced by breast cancer survivorship.


Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Atenção Plena , Feminino , Humanos , Sobreviventes de Câncer/psicologia , Atenção Plena/métodos , Estudos Cross-Over , Sobreviventes/psicologia , Neoplasias da Mama/psicologia , Fadiga/psicologia , Dor/complicações , Qualidade de Vida/psicologia
4.
Int J Behav Med ; 30(4): 463-472, 2023 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35831698

RESUMO

BACKGROUND: Psychological disorders can substantially worsen physical symptoms associated with breast cancer diagnosis and treatment, reducing survivors' quality of life and increasing recurrence risk. Distress disorders may be particularly detrimental given their physical correlates. Across two studies, we examined the relationship between a distress disorder history and physical symptoms pre- and post-adjuvant treatment - two important periods of the cancer trajectory. METHODS: Breast cancer patients awaiting adjuvant treatment (n = 147; mean age = 52.54) in study 1 and survivors 1-10 years post-treatment (n = 183; mean age = 56.11) in study 2 completed a diagnostic interview assessing lifetime presence of psychological disorders. They also rated their pain, fatigue, physical functioning, and self-rated health. Covariates included body mass index, age, cancer stage, menopause status, and physical comorbidities. RESULTS: Results from both studies indicated that a distress disorder history was associated with higher pain, fatigue, and sleep difficulties as well as lower self-rated health compared to those without such a history. CONCLUSIONS: These findings suggest that breast cancer survivors with a distress disorder may be particularly at risk for more physical symptoms, poorer sleep, and worse self-rated health both prior to and following adjuvant treatment.


Assuntos
Neoplasias da Mama , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias da Mama/complicações , Neoplasias da Mama/psicologia , Qualidade de Vida/psicologia , Ansiedade/psicologia , Sobreviventes/psicologia , Dor , Fadiga/epidemiologia , Fadiga/etiologia
5.
Brain Behav Immun ; 103: 1-9, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35378230

RESUMO

PURPOSE: To investigate breast cancer survivors' inflammatory responses to typhoid vaccine as a window into their innate immune response to novel pathogens. METHODS: This double-blind crossover trial randomized 158 breast cancer survivors to either the vaccine/saline placebo or the placebo/vaccine sequence. The relative contributions of age, cardiorespiratory fitness (VO2peak), type of cancer treatment, central obesity, and depression to interleukin (IL)-6, IL-1 receptor antagonist (IL-1Ra), and WBC vaccine responses were assessed pre-injection and 1.5, 3, 4.5, 6, and 7.5 h post-injection. RESULTS: The vaccine produced larger IL-6, IL-1Ra, and WBC responses than placebo, ps < 0.0001. Prior chemotherapy, higher central obesity, and lower VO2peak were associated with smaller vaccine responses after controlling for baseline inflammation. Vaccine response was summarized by the percent increase in area under the curve (IL-6, WBC) or average post-injection mean (IL-1Ra) for vaccine relative to placebo. Women who received chemotherapy had smaller vaccine responses than women who did not for both IL-6 (44% vs 78%, p <.001) and WBC (26% vs 40%, p <.001); IL-1ra response was not significantly moderated by chemotherapy. Women whose central adiposity was one standard deviation above the mean had smaller vaccine responses than women with average adiposity for IL-6 (33% vs 54%, p <.001), WBC (20% vs 30%, p <.001), and IL-1Ra (2.0% vs 3.2%, p <.001). Women with an average level of VO2peak had smaller vaccine responses than women whose VO2peak was one standard deviation above the mean for IL-6 (54% vs 73%, p <.001), WBC (30% vs 40%, p <.001), and IL-1Ra (3.2% vs. 4.1%, p = 0.01). Age and depression did not significantly moderate vaccine responses. CONCLUSIONS: This study provided novel data on chemotherapy's longer-term adverse immune consequences. The data also have an important public health message: even relatively low levels of fitness can benefit the innate immune response to a vaccine.


Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Vacinas Tíficas-Paratíficas , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-6 , Obesidade , Obesidade Abdominal/tratamento farmacológico
6.
J Behav Med ; 44(2): 253-259, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33135103

RESUMO

A number of studies have shown that self-rated health reliably predicts mortality. This study assessed the impact of perseveration on self-rated health, physical functioning, and physical symptoms (pain, fatigue, breast cancer symptoms) among breast cancer patients. We hypothesized that cancer-related distress would serve as an intervening variable between both worry and rumination and self-rated health, physical functioning, and physical symptoms. Women (N = 124) who were approximately 7 weeks post-surgery but pre adjuvant treatment completed the Impact of Events Scale, the Penn State Worry Questionnaire, and the Rumination Scale. They also rated their pain, fatigue, physical functioning, and self-rated health using the RAND-36 and breast cancer symptoms with the Breast Cancer Prevention Trial Symptom Checklist (BCPT). Covariates included body mass index, age, cancer stage, menopause status, and physical comorbidities. Worry was associated with higher cancer-related distress, which in turn predicted greater pain and breast cancer symptoms, poorer physical functioning, and lower self-rated health. Rumination also predicted greater cancer-related distress, which ultimately contributed to greater pain along with poorer physical functioning and self-rated health. Models with fatigue as an outcome were not significant. These findings suggest that perseveration can heighten cancer-related distress and subsequent perceptions of physical symptoms and health among breast cancer patients prior to adjuvant treatment. Perseveration early in the cancer trajectory can adversely increase the impact of a cancer diagnosis and treatment on functioning and quality of life.


Assuntos
Neoplasias da Mama , Ansiedade , Neoplasias da Mama/complicações , Fadiga/etiologia , Feminino , Humanos , Dor , Qualidade de Vida , Inquéritos e Questionários
7.
Support Care Cancer ; 28(8): 3669-3677, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31811486

RESUMO

PURPOSE: Fractional CO2 laser therapy is an emerging treatment for genitourinary syndrome of menopause (GSM). The objective of this study was to determine the feasibility and preliminary efficacy of fractional CO2 laser therapy in breast cancer survivors. METHODS: This was a single arm feasibility study of breast cancer survivors with dyspareunia and/or vaginal dryness. Participants received three treatments of fractional CO2 laser therapy at 30-day intervals and returned for a 1-month follow-up. Feasibility was defined as treatment completion without serious adverse events (SAE) in 80% of patients. We collected data on the Vaginal Assessment Scale (VAS), the Female Sexual Function Index (FSFI), the Urinary Distress Index (UDI), and SAE. RESULTS: A total of 64 patients participated in the study. The majority of women had Estrogen receptor/Progesterone receptor (ER/PR) positive/Her2neu negative (n = 37; 63%), stage I (n = 32, 54%) or II (n = 19, 32%) breast cancer. Most were receiving endocrine therapy (n = 54, 92%), most commonly aromatase inhibitors (AI; n = 40, 68%). Fifty-nine (88.1%) of those enrolled completed all treatments according to protocol with no reported SAE. No patient withdrew due to SAE. The scores of the VAS (mean Δ - 0.99; 95% CI [- 1.19, - 0.79], p < 0.001)), FSFI (mean Δ 9.67; 95% CI [7.27, 12.1], p < 0.001), and UDI (mean Δ - 8.85; 95% CI [- 12.75, - 4.75], p < 0.001)) improved from baseline to follow-up. CONCLUSION: Fractional CO2 laser treatment for breast cancer survivors is feasible and appears to reduce GSM symptoms across treatment and follow-up.


Assuntos
Neoplasias da Mama/complicações , Doenças Urogenitais Femininas/etiologia , Doenças Urogenitais Femininas/terapia , Terapia a Laser/métodos , Neoplasias da Mama/metabolismo , Sobreviventes de Câncer , Dispareunia/terapia , Feminino , Humanos , Lasers de Gás , Menopausa , Pessoa de Meia-Idade , Receptores de Progesterona/metabolismo , Síndrome , Resultado do Tratamento , Doenças Vaginais
8.
World J Oncol ; 15(3): 337-347, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38751708

RESUMO

Dyspnea is a disabling symptom presented in approximately half of all cancer survivors. From a clinical perspective, despite the availability of pharmacotherapies, evidence-based effective treatments are limited for relieving dyspnea in cancer survivors. Preliminary evidence supports the potential of respiratory muscle training to reduce dyspnea in cancer survivors, although large randomized controlled studies are warranted. The aims of this article were to review the relevant scientific literature on the potential therapeutic role of respiratory muscle training in dyspnea management of cancer survivor, and to identify possible mechanisms, strengths and limitations of the evidence as well as important gaps for future research directions.

9.
NPJ Breast Cancer ; 10(1): 49, 2024 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-38898072

RESUMO

There is limited data regarding the added benefit of adjuvant systemic therapy in the management of small, node-negative, HER2+ breast cancer. In a multi-institutional retrospective analysis using the American Society of Clinical Oncology CancerLinQ database, we compared survival outcomes among T1a-c N0 HER2+ patients diagnosed between 2010 to 2021 who received locoregional therapy alone or in combination with adjuvant trastuzumab (+/- chemotherapy). Primary outcomes were invasive disease-free survival (iDFS) and overall survival (OS). Of the 1,184 patients, 436 received locoregional therapy alone. We found a statistically significant improvement in iDFS (HR 0.73, P = 0.003) and OS (HR 0.63, P = 0.023) on univariate analysis with adjuvant trastuzumab with or without chemotherapy which remained statistically significant on multivariate analysis. Three-arm univariate analysis found that iDFS was significantly improved with trastuzumab monotherapy (P = 0.003) and combination therapy (P = 0.027) compared to observation. Subgroup data suggests that T1b/c tumors derive the greatest benefit.

10.
J Affect Disord ; 342: 1-9, 2023 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-37683942

RESUMO

BACKGROUND: Prior evidence has linked inflammation with impulsivity, but most of this evidence is cross-sectional. In this study, we provoked an acute inflammatory cytokine response to see whether it lowered prepotent response inhibition on three cognitive tasks. METHOD: This study features secondary analyses from a randomized crossover trial in which 171 postmenopausal breast cancer survivors (Stage I-IIIA) each received a typhoid capsular polysaccharide vaccination and a saline placebo injection in a random sequence at two separate visits at least one month apart. Participants completed the Stroop Color-Discrepant Task, the 2-back, and the Conners Continuous Performance Test (CPT) on the computer between 5 and 7 h after the injections. They had their blood drawn once before and repeatedly after the injection to measure interleukin-1 receptor antagonist and interleukin-6 responses. RESULTS: Women committed marginally fewer errors on the Stroop color-discrepant trials after the typhoid vaccine (M = 0.36, SE = 0.08), compared to placebo (M = 0.54, SE = 0.09, p = .076). Injection type did not predict 2-back accuracy (p = .80) or CPT commission errors (p = .47). Inflammatory cytokine responses were also unrelated to the outcomes of interest (ps>.16). CONCLUSION: We found no evidence that an acute inflammatory cytokine response provokes response disinhibition - an important facet of impulsivity. In fact, our only marginally non-significant result suggested that women were better able to inhibit their prepotent responses on the Stroop after receiving the typhoid vaccine, compared to placebo. Further experimental tests of the acute inflammatory cytokine response's effect on other aspects of impulsivity are warranted. LIMITATIONS: The sample was female, primarily White, highly educated cancer survivors, and recruitment was not premised on impulsive traits or diagnosis with an impulsive-related disorder. Also, there are many facets of impulsivity, and this study only measured response inhibition.


Assuntos
Citocinas , Vacinas Tíficas-Paratíficas , Humanos , Feminino , Estudos Transversais , Inibição Psicológica , Comportamento Impulsivo/fisiologia , Inflamação
11.
Cancers (Basel) ; 15(6)2023 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-36980642

RESUMO

We evaluated associations of the Empirical Dietary Index for Hyperinsulinemia (EDIH), Empirical Dietary Inflammatory Pattern (EDIP) and Healthy Eating Index (HEI2015) and their metabolomics profiles with the risk of total and site-specific cancers. We used baseline food frequency questionnaires to calculate dietary scores among 112,468 postmenopausal women in the Women's Health Initiative. We used multivariable-adjusted Cox regression to estimate hazard ratios (HR) and 95% confidence intervals for cancer risk estimation. Metabolomic profile scores were derived using elastic-net regression with leave-one-out cross validation. In over 17.8 years, 18,768 incident invasive cancers were adjudicated. Higher EDIH and EDIP scores were associated with greater total cancer risk, and higher HEI-2015 with lower risk: HRQ5vsQ1(95% CI): EDIH, 1.10 (1.04-1.15); EDIP, 1.08 (1.02-1.15); HEI-2015, 0.93 (0.89-0.98). The multivariable-adjusted incidence rate difference(Q5vsQ1) for total cancer was: +52 (EDIH), +41 (EDIP) and -49 (HEI-2015) per 100,000 person years. All three indices were associated with colorectal cancer, and EDIH and EDIP with endometrial and breast cancer risk. EDIH was further associated with luminal-B, ER-negative and triple negative breast cancer subtypes. Dietary patterns contributing to hyperinsulinemia and inflammation were associated with greater cancer risk, and higher overall dietary quality, with lower risk. The findings warrant the testing of these dietary patterns in clinical trials for cancer prevention among postmenopausal women.

12.
Cancers (Basel) ; 15(17)2023 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-37686689

RESUMO

About one-in-three breast cancer survivors have lingering cognitive complaints and objective cognitive impairment. Chronic inflammation and intestinal permeability (i.e., leaky gut), two risk factors for cognitive decline, can also fuel depression-another vulnerability for cognitive decline. The current study tested whether depression accompanied by high levels of inflammation or intestinal permeability predicted lower subjective and objective cognitive function in breast cancer survivors. We combined data from four breast cancer survivor studies (n = 613); some had repeated measurements for a total of 1015 study visits. All participants had a blood draw to obtain baseline measures of lipopolysaccharide binding protein-a measure of intestinal permeability, as well as three inflammatory markers that were incorporated into an inflammatory index: C-reactive protein, interleukin-6, and tumor necrosis factor-α. They reported depressive symptoms on the Center for Epidemiological Studies depression scale (CES-D), and a binary variable indicated clinically significant depressive symptoms (CES-D ≥ 16). The Kohli (749 observations) and the Breast Cancer Prevention Trial (591 observations) scales assessed subjective cognitive function. Objective cognitive function tests included the trail-making test, Hopkins verbal learning test, Conners continuous performance test, n-back test, FAS test, and animal-naming test (239-246 observations). Adjusting for education, age, BMI, cancer treatment type, time since treatment, study visit, and fatigue, women who had clinically elevated depressive symptoms accompanied by heightened inflammation or intestinal permeability reported poorer focus and marginally poorer memory. However, poorer performance across objective cognitive measures was not specific to inflammation-associated depression. Rather, there was some evidence of lower verbal fluency; poorer attention, verbal learning and memory, and working memory; and difficulties with visuospatial search among depressed survivors, regardless of inflammation. By themselves, inflammation and intestinal permeability less consistently predicted subjective or objective cognitive function. Breast cancer survivors with clinically significant depressive symptoms accompanied by either elevated inflammation or intestinal permeability may perceive greater cognitive difficulty, even though depression-related objective cognitive deficits may not be specific to inflammation- or leaky-gut-associated depression.

13.
Ther Adv Med Oncol ; 15: 17588359231217976, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38152697

RESUMO

Background: Heat shock protein 90 (HSP90) is a molecular chaperone required for stabilization of client proteins over-activated in triple-negative breast cancer (TNBC). Over-expression of HSP90 client proteins has been implicated in paclitaxel resistance. Onalespib (AT13387) is a potent inhibitor of HSP90 that could improve paclitaxel efficacy when administered in combination. Design: This phase Ib trial administered onalespib with paclitaxel in patients with advanced TNBC to assess safety and establish a recommended phase II dose (RP2D). Objectives: The primary objectives were determining the dose-limiting toxicities and maximum tolerated dose of combination therapy. Secondary objectives included pharmacokinetic (PK) analysis and determination of overall response rate (ORR), duration of response (DOR), and progression-free survival (PFS). Methods: Patients with advanced TNBC were treated with standard dose intravenous paclitaxel in combination with intravenous onalespib at doses ranging from 120 to 260 mg/m2 administered on days 1, 8, and 15 of a 28-day cycle using a standard 3 + 3 design. A total of 15 patients were enrolled to dose expansion cohort at RP2D to confirm safety profile. Results: Thirty-one patients were enrolled in the study, of which over 90% had received prior taxane therapy. Paclitaxel was given for metastatic disease in 23% of patients. Adverse events (AEs) included anemia (grade 3: 20%), lymphopenia (grade 3: 17%), and neutropenia (grade 3: 33%, grade 4: 4%). The most frequent grade ⩾3 non-hematologic AE was diarrhea (7%). The established RP2D was 260 mg/m2 onalespib when given with paclitaxel at 80 mg/m2. PK analysis revealed a modest drug interaction profile for onalespib in the combination regimen. ORR was 20%. Three patients achieved complete responses, all of whom had received prior taxane therapy. Median DOR was 5.6 months; median PFS was 2.9 months. Conclusion: Combination treatment with onalespib and paclitaxel had an acceptable toxicity profile and RP2D was determined to be 260 mg/m2 of onalespib. Combination therapy showed antitumor activity in patients with advanced TNBC. Trial registration: Onalespib and paclitaxel in treating patients with advanced TNBC https://clinicaltrials.gov/ct2/show/NCT02474173.


Phase 1b study of HSP90 inhibitor called onalespib in combination with paclitaxel in patients with advanced triple-negative breast cancer This Phase 1b study demonstrated that treatment with a combination of onalespib and paclitaxel was reasonably well tolerated by most patients. Onalespib at 260 mg/m2 given intravenously on days 1, 8 and 15 on 28-day cycles in combination with standard dose and schedule of paclitaxel was established as the recommended phase 2 dose for further clinical development. Despite minor drug-drug interactions between these 2 agents, onalespib did not alter paclitaxel exposure and paclitaxel did not affect exposure to onalespib. While onalespib with paclitaxel combination therapy did not yield durable objective responses or prolonged progression-free survival, there were several patients with long-lasting benefit from this combination including patients who previously experienced progression on taxane therapy.

14.
Front Oncol ; 12: 857590, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35574319

RESUMO

Background: Among women, breast cancer is the leading cause of cancer-related death worldwide. Estrogen receptor α-positive (ERα+) breast cancer accounts for 70% of all breast cancer subtypes. Although ERα+ breast cancer initially responds to estrogen deprivation or blockade, the emergence of resistance compels the use of more aggressive therapies. While ERα is a driver in ERα+ breast cancer, ERß plays an inhibitory role in several different cancer types. To date, the lack of highly selective ERß agonists without ERα activity has limited the exploration of ERß activation as a strategy for ERα+ breast cancer. Methods: We measured the expression levels of ESR1 and ESR2 genes in immortalized mammary epithelial cells and different breast cancer cell lines. The viability of ERα+ breast cancer cell lines upon treatments with specific ERß agonists, including OSU-ERb-12 and LY500307, was assessed. The specificity of the ERß agonists, OSU-ERb-12 and LY500307, was confirmed by reporter assays. The effects of ERß agonists on cell proliferation, cell cycle, apoptosis, colony formation, cell migration, and expression of tumor suppressor proteins were analyzed. The expression of ESR2 and genes containing ERE-AP1 composite response elements was examined in ERα+ human breast cancer samples to determine the correlation between ESR2 expression and overall survival and that of putative ESR2-regulated genes. Results: In this study, we demonstrate the efficacy of highly selective ERß agonists in ERα+ breast cancer cell lines and drug-resistant derivatives. ERß agonists blocked cell proliferation, migration, and colony formation and induced apoptosis and S and/or G2/M cell-cycle arrest of ERα+ breast cancer cell lines. Also, increases in the expression of the key tumor suppressors FOXO1 and FOXO3a were noted. Importantly, the strong synergy between ERß agonists and ERα antagonists suggested that the efficacy of ERß agonists is maximized by combination with ERα blockade. Lastly, ESR2 (ERß gene) expression was negatively correlated with ESR1 (ERα gene) and CCND1 RNA expression in human metastatic ERα+/HER2- breast cancer samples. Conclusion: Our results demonstrate that highly selective ERß agonists attenuate the viability of ERα+ breast cancer cell lines in vitro and suggest that this therapeutic strategy merits further evaluation for ERα+ breast cancer.

15.
J Clin Med ; 11(3)2022 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-35160226

RESUMO

(1) Background: The objective of this study was to determine the long-term efficacy of fractional CO2 laser therapy in breast cancer survivors. (2) Methods: This was a single-arm study of breast cancer survivors. Participants received three treatments of fractional CO2 laser therapy and returned for a 4 week follow-up. Participants were contacted for follow-up at annual intervals. The Vaginal Assessment Scale (VAS), the Female Sexual Function Index (FSFI), the Female Sexual Distress Scare Revised (FSDS-R), the Urinary Distress Inventory (UDI), and adverse events were collected and reported for the two-year follow-up. The changes in scores were compared between the four-week and two-year and the one-year and two-year follow-ups using paired t-tests. (3) Results: In total, 67 BC survivors were enrolled, 59 completed treatments and the four week follow-up, 39 participated in the one-year follow-up, and 33 participated in the two-year follow-up. After initial improvement in the VAS from baseline to the four week follow-up, there was no statistically significant difference in the VAS score (mean Δ 0.23; 95% CI [-0.05, 0.51], p = 0.150) between the four week follow-up and the two-year follow-up. At the two-year follow-up, the FSFI and FSDS-R scores remained improved from baseline and there was no statistically significant change in the FSFI score (mean Δ -0.83; 95% CI [-3.07, 2.38] p = 0.794) or the FSDS-R score (mean Δ -2.85; 95% CI [-1.88, 7.59] p = 0.227) from the one to two-year follow-up. The UDI scores approached baseline at the two-year follow-up; however, the change between the one- and two-year follow-ups was not statistically significant (mean Δ 4.76; 95% CI [-1.89, 11.41], p = 0.15). (4) Conclusions: Breast cancer survivors treated with fractional CO2 laser therapy have sustained improvement in sexual function two years after treatment completion, suggesting potential long-term benefit.

16.
J Oncol ; 2021: 9965583, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34135964

RESUMO

PURPOSE: The purpose of this study was to determine the feasibility and preliminary efficacy of a cardiac rehabilitation (CR) intervention in the breast cancer population. METHODS: This single-arm feasibility study evaluated a 14-week CR intervention program in breast cancer survivors. Feasibility was defined as completion of at least 30/36 sessions of the program without serious adverse events (SAE) in 80% of patients. Secondary endpoints included the change in VO2 max, cardiovascular disease (CVD) risk factors, Duke Activity Secondary Index (DASI), Brief Fatigue Inventory (BFI), and QLQ-C30. All outcomes were reported as mean change and compared using paired t-tests. RESULTS: A total of 25 patients were enrolled in the study. 18 patients of the 25 enrolled (72%) completed the 14 weeks program without SAE. The overall adherence to the study protocol was 60%. Of the 18 participants who did not withdraw from the program, 15 (83%) adhered to the study protocol and completed 30 or more sessions. There was a nonsignificant improvement in VO2 max (mean Δ0.5, p=0.6). The scores for DASI, BFI, and QLQ-C30 improved from baseline to posttreatment. CONCLUSION: A CR intervention in breast cancer survivors had high adherence in those who were able to complete the 14-week program. The program significantly improved patient reported physical activity, fatigue, and quality of life (QoL), without significant improvement in CVD risk factors. Implications for cancer patients are that early implementation of a CR program should be considered by practitioners as it improves QoL and exercise tolerance in breast cancer survivors.

17.
Clin Cancer Res ; 27(21): 5810-5817, 2021 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-34400413

RESUMO

PURPOSE: Fatty acid synthase (FASN) is overexpressed in 70% of operable triple-negative breast cancer (TNBC) and is associated with poor prognosis. Proton pump inhibitors selectively inhibit FASN activity and induce apoptosis in TNBC cell lines. PATIENTS AND METHODS: Patients with operable TNBC were enrolled in this single-arm phase II study. Patients began omeprazole 80 mg orally twice daily for 4-7 days prior to neoadjuvant anthracycline-taxane-based chemotherapy (AC-T) and continued until surgery. The primary endpoint was pathologic complete response (pCR) in patients with baseline FASN overexpression (FASN+). Secondary endpoints included pCR in all surgery patients, change in FASN expression, enzyme activity, and downstream protein expression after omeprazole monotherapy, safety, and limited omeprazole pharmacokinetics. RESULTS: Forty-two patients were recruited with a median age of 51 years (28-72). Most patients had ≥cT2 (33, 79%) and ≥N1 (22, 52%) disease. FASN overexpression prior to AC-T was identified in 29 of 34 (85%) evaluable samples. The pCR rate was 72.4% [95% confidence interval (CI), 52.8-87.3] in FASN+ patients and 74.4% (95% CI, 57.9-87.0) in all surgery patients. Peak omeprazole concentration was significantly higher than the IC50 for FASN inhibition observed in preclinical testing; FASN expression significantly decreased with omeprazole monotherapy [mean change 0.12 (SD, 0.25); P = 0.02]. Omeprazole was well tolerated with no grade ≥ 3 toxicities. CONCLUSIONS: FASN is commonly expressed in early TNBC. Omeprazole can be safely administered in doses that inhibit FASN. The addition of omeprazole to neoadjuvant AC-T yields a promising pCR rate that needs further confirmation in randomized studies.


Assuntos
Ácido Graxo Sintases/antagonistas & inibidores , Terapia Neoadjuvante , Omeprazol/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Omeprazol/farmacologia , Resultado do Tratamento
18.
Menopause ; 28(6): 642-649, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33534429

RESUMO

OBJECTIVE: The objective of this pilot study was to evaluate the change in sexual function following treatment with fractional CO2 laser therapy in breast cancer (BC) survivors with genitourinary syndrome of menopause (GSM). METHODS: A single-arm feasibility study of BC survivors with symptoms of GSM, including dyspareunia and/or vaginal dryness, was conducted. Participants who received three treatments with fractional CO2 laser and 4-week follow-up were contacted for patient-reported outcomes and adverse events at 12 months. Sexual function was measured using the Female Sexual Function Index (FSFI) and Female Sexual Distress Scale Revised (FSDS-R). Descriptive statistics were calculated for patient demographics and disease characteristics for the set of participants who agreed to long-term follow-up and those who were lost to follow-up. FSFI and FSDS-R scores were summarized at baseline, 4 weeks and 12 months, as well as the change from baseline, and were compared using a Wilcoxon signed rank test. RESULTS: A total of 67 BC survivors enrolled, 59 completed treatments and 4-week follow-up; 39 participated in the 12 month follow-up. The overall FSFI score improved from baseline to 4-week follow-up (median Δ 8.8 [Q1, Q3] (QS) (2.2, 16.7)], P < 0.001). There were improvements at 4 weeks in all domains of the FSFI (P < 0.001 for each) including desire (median Δ 1.2; QS [0.6, 1.8]), arousal (median Δ 1.2; QS [0.3, 2.7]), lubrication (median Δ 1.8 (0, 3.3), orgasm (median Δ 1.2; QS [0, 3.6]), satisfaction (median Δ 1.6 (0.4, 3.2)), and pain (median Δ 1.6 (0, 3.6). The FSDS-R score also improved from baseline to 4-week follow-up (median Δ -10.0; QS [-16, -5] P < 0.001) indicating less sexually related distress. The scores of the FSFI and FSDS-R remained improved at 12 months and there were no serious adverse events reported. CONCLUSIONS: In BC survivors with GSM, the total and individual domain scores of the FSFI and the FSDS-R improved after fractional CO2 laser therapy.


Video Summary:http://links.lww.com/MENO/A711 .


Assuntos
Neoplasias da Mama , Sobreviventes de Câncer , Doenças Urogenitais Femininas , Terapia a Laser , Lasers de Gás , Neoplasias da Mama/radioterapia , Dióxido de Carbono , Feminino , Doenças Urogenitais Femininas/etiologia , Doenças Urogenitais Femininas/cirurgia , Humanos , Lasers de Gás/uso terapêutico , Menopausa , Medidas de Resultados Relatados pelo Paciente , Projetos Piloto , Síndrome
19.
Womens Health (Lond) ; 11(3): 281-94, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26102468

RESUMO

Breast cancer is the most common form of cancer and the second leading cause of cancer deaths among women in the USA. A quarter of all newly diagnosed cases are characterized by overexpression of HER-2 which is associated with poor prognosis. In March 2007, lapatinib, an oral dual-tyrosine kinase inhibitor was approved in combination with capecitabine for metastatic HER-2-positive breast cancer that has progressed on prior trastuzumab therapy, and in combination with letrozole for postmenopausal women with HER-2 and hormone receptor-positive advanced breast cancer. In the future, lapatinib may play an important role in dual HER-2 blockade with trastuzumab and other targeted agents for women with HER-2-overexpressing breast cancer.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/genética , Feminino , Humanos , Lapatinib , Pós-Menopausa , Estados Unidos , Saúde da Mulher
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