RESUMO
PURPOSE: Leptomeningeal metastases (LM) are an aggressive complication of metastatic breast cancer (MBC) with brain metastases (BM), with a short survival of weeks to months. Studies suggest that surgical resection of BM may increase the risk of LM, especially in infratentorial metastases. In this retrospective study, we examine this and other factors which may be associated with increased risk of LM. METHODS: A database search at a single institution identified 178 patients with MBC and treated BM between 2007 and 2020. We collected demographic, clinical, radiographic, and other treatment data. LM was diagnosed by cerebrospinal fluid (CSF) cytology, neuroimaging, or both. Cox proportional hazards model was used. RESULTS: After a median follow-up of 8.5 months, 41 out of 178 patients (23%) with BM developed LM. Median time to develop LM was 130 days. Mean age was 51.3 years. The number and size of the BM, hemorrhagic/cystic lesions, progressive/stable systemic disease, and extracranial metastases sites other than liver did not pose a higher risk of LM. Infratentorial lesions (HR = 5.41) and liver metastases (HR = 2.28) had a higher risk of LM. Patients who had any surgery did not have a higher risk for LM (HR 1.13). The LM group had a worse overall survival as compared to the non-LM group. CONCLUSION: Among MBC patients with BM, infratentorial BM and visceral liver lesions increase the risk of LM, whereas local treatment modalities such as surgery and radiation do not. These data imply that local treatment strategy should not differ based on potential risk for LM.
Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Carcinomatose Meníngea , Neoplasias Encefálicas/secundário , Neoplasias Encefálicas/terapia , Neoplasias da Mama/patologia , Feminino , Humanos , Carcinomatose Meníngea/secundário , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
PURPOSE: This study evaluated the proportion of premenopausal women who experience persistent ovarian escape (OE) while receiving ovarian suppression (OS) therapy for estrogen receptor-positive (ER+) breast cancer treatment. The study also examined clinical factors that may predispose to higher risk of persistent OE. MATERIALS AND METHODS: This was a retrospective, "real-world" study to evaluate premenopausal women receiving adjuvant endocrine OS therapy. The primary objective was to measure the percentage of persistent OE within the first 3 months of OS injections (using either leuprolide or goserelin). The secondary objective was to associate baseline clinical data (age, body mass index [BMI], and previous chemotherapy) with the probability of OE. RESULTS: Of the 46 patients included in this analysis, 11 (23.9%) women did not achieve OS within 3 months. Three women (6.5%) remained in OE at 12 months. Older age (odds ratio, 0.86; confidence interval, 0.76-0.98, p = .024) was associated with lower chance of developing OE. BMI, previous chemotherapy, and drug used (tamoxifen versus aromatase inhibitor) did not correlate with the likelihood of OE in this patient cohort. CONCLUSION: Among the premenopausal women who did not attain complete ovarian suppression, young age was a significant risk factor for likelihood of OE. Although the clinical relevance of this finding is not yet known, it should prompt further studies to determine whether inadequate OS is associated with higher recurrence risk for patients with ER+ breast cancer. IMPLICATIONS FOR PRACTICE: Because up to a quarter of premenopausal women do not attain adequate ovarian suppression within the first 3 months of gonadotropin-releasing hormone (GnRH) agonist therapy, bloodwork should be checked to ascertain hormone levels prior to starting aromatase inhibitor therapy, and at regular intervals, for these women.
Assuntos
Neoplasias da Mama , Idoso , Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Feminino , Humanos , Receptores de Estrogênio , Estudos Retrospectivos , Tamoxifeno/uso terapêuticoRESUMO
INTRODUCTION: Neoadjuvant endocrine therapy is often utilized to downstage Estrogen Receptor-positive (ER+) breast cancer prior to surgery. However, this approach is sometimes met with endocrine resistance mechanisms within the tumor. This trial examines the safety and efficacy of tamoxifen in combination with an mTORC1/2 inhibitor, TAK-228, in the neoadjuvant treatment of ER+ breast cancer. METHODS: In this single-arm, open-label trial, pre- and post-menopausal women were enrolled to receive neoadjuvant tamoxifen (20 mg daily) with TAK-228 (30 mg weekly) for 16 weeks prior to surgery. Patient had tissue sampling at baseline, week 6, and week 16. The primary endpoint was change in Ki-67 from baseline to 6 weeks. The toxicity, change in tumor size, pathologic complete response rate, PEPI score, and baseline Oncotype Dx score were also assessed. RESULTS: Twenty-eight women were enrolled on the trial, and 25 completed the entire study course. The combination of tamoxifen and TAK-228 resulted in a significant reduction in Ki-67 from 18.3 to 15.2% (p = 0.0023). The drug was also found to be safe and tolerable. While nausea and hyperglycemia were common side effects, these were manageable. The tumor size also significantly decreased with the treatment, with a median decrease of 0.75 cm (p < 0.0001). There were no pathologic complete responses. CONCLUSION: Tamoxifen and TAK-228 was safe and well tolerated neoadjuvant treatment for ER+ breast cancer, preliminary evidence of activity with significant reduction in both Ki-67 and tumor size, warranting further evaluation in a larger study.
Assuntos
Neoplasias da Mama , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzoxazóis , Neoplasias da Mama/tratamento farmacológico , Feminino , Hormônios/uso terapêutico , Humanos , Nitrilas/uso terapêutico , Pirimidinas , Receptor ErbB-2/genética , Receptores de Estrogênio , Tamoxifeno/uso terapêutico , Resultado do Tratamento , Triazóis/uso terapêuticoRESUMO
BACKGROUND: In invasive breast cancer, HER2 is a well-established negative prognostic factor. However, its significance on the prognosis of ductal carcinoma in situ (DCIS) of the breast is unclear. As a result, the impact of HER2-directed therapy on HER2-positive DCIS is unknown and is currently the subject of ongoing clinical trials. In this study, we aim to determine the possible impact of HER 2-directed targeted therapy on survival outcomes for HER2-positive DCIS patients. MATERIALS AND METHODS: The National Cancer Data Base (NCDB) was used to retrieve patients with biopsy-proven DCIS diagnosed from 2004-2015. Patients were divided into two groups based on the adjuvant therapy they received: systemic HER2-directed targeted therapy or no systemic therapy. Statistics included multivariable logistic regression to determine factors predictive of receiving systemic therapy, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling to determine variables associated with OS. RESULTS: Altogether, 1927 patients met inclusion criteria; 430 (22.3%) received HER2-directed targeted therapy; 1497 (77.7%) did not. Patients who received HER2-directed targeted therapy had a higher 5-year OS compared to patients that did not (97.7% vs. 95.8%, p = 0.043). This survival benefit remained on multivariable analysis. Factors associated with worse OS on multivariable analysis included Charlson-Deyo Comorbidity Score ≥ 2 and no receipt of hormonal therapy. CONCLUSION: In this large study evaluating HER2-positive DCIS patients, the receipt of HER2-directed targeted therapy was associated with an improvement in OS. The results of currently ongoing clinical trials are needed to confirm this finding.
RESUMO
PURPOSE: Half of hormone receptor-positive (HR+) breast cancer patients will develop joint pain, termed aromatase inhibitor-induced arthralgia (AIA), while taking aromatase inhibitor therapy. Though there is no universally accepted effective treatment for AIA, there has been some evidence to support high-dose vitamin D as a treatment. METHODS: We randomized post-menopausal women who were beginning adjuvant AI therapy to receive standard-dose vitamin D3 (800 IU daily for 52 weeks), or high-dose vitamin D3 (50,000 IU weekly for 12 weeks, followed by 2000 IU daily for 40 weeks). The primary end point was development of AIA. The trial was designed to enroll 184 patients. This futility analysis was performed after 93 patients were enrolled. RESULTS: The high-dose vitamin D regimen was effective in raising serum vitamin D levels, but there was no significant difference in development of AIA between the two arms. In the high-dose arm, 25 patients (54%) developed AIA, compared to 27 patients (57%) in the standard-dose arm. The planned futility analysis was positive; thus, the study was terminated. Neither baseline vitamin D nor 12-week vitamin D level was predictive of AIA development. CONCLUSION: Although vitamin D levels were increased in the high-dose arm, there was no significant signal for benefit of high-dose vitamin D supplementation for AIA prevention in this unblinded trial. This study, along with several others, implies that vitamin D likely does not play a significant role in AIA for the majority of patients.
Assuntos
Antineoplásicos Hormonais/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Artralgia/etiologia , Artralgia/prevenção & controle , Neoplasias da Mama/complicações , Colecalciferol/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Artralgia/diagnóstico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Suplementos Nutricionais , Feminino , Humanos , Adesão à Medicação , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Fatores de Risco , Resultado do TratamentoRESUMO
PURPOSE OF REVIEW: Aromatase inhibitor-induced arthralgia (AIA) is a very common syndrome which significantly affects breast cancer survivors' quality of life, and it often leads to non-compliance with aromatase inhibitor (AI) therapy. However, the treatment of AIA remains a clinical challenge. Here, we will review the current data for acupuncture and vitamin D in the management of AIA. RECENT FINDINGS: Acupuncture has been shown to improve AIA symptoms, but it has not consistently been proven to offer significantly more clinical benefit than sham acupuncture. Similarly, while some vitamin D trials have shown benefit, the studies have not consistently shown improvement in AIA symptoms. Neither acupuncture nor vitamin D can be touted as standard treatments for AIA. However, many patients do experience subjective improvement of their symptoms with these therapies. When other treatments, such as exercise and duloxetine, are not feasible or not effective, it is reasonable to offer a trial of acupuncture or vitamin D to patients who are suffering from AIA, as the potential harms are very few, and they do offer possible relief from AIA symptoms.
Assuntos
Terapia por Acupuntura , Inibidores da Aromatase/efeitos adversos , Artralgia/induzido quimicamente , Artralgia/terapia , Vitamina D/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Sobreviventes de Câncer , Feminino , Humanos , Qualidade de Vida , Resultado do TratamentoRESUMO
BACKGROUND: Although randomized data support omitting adjuvant radiotherapy (RT) following breast conservation for T1-2N0 estrogen receptor positive breast cancer in ≥70-year-old women, there remains a knowledge gap regarding its omission for triple-negative BC (TNBC). METHODS AND MATERIALS: The National Cancer Database (NCDB) was queried for ≥70-year-old females with newly diagnosed T1-2N0M0 TNBC treated with breast conservation. Multivariable logistic regression ascertained factors associated with adjuvant RT administration. Overall survival (OS) between patients treated with or without adjuvant RT was estimated using the Kaplan-Meier method. Cox proportional hazards modeling determined variables associated with OS. RESULTS: Of 8526 patients, 6283 (74%) patients received adjuvant RT, and 2243 (26%) did not. RT was more frequently withheld in older patients, those with higher comorbidities, lower income, pT2 disease, following margin-positive resection, receipt of chemotherapy, and at academic centers (P < 0.05 for all). Median follow-up was 38.0 months. Five-year OS was greater in the adjuvant RT group (77.2% vs 55.3%, P < 0.001); these differences persisted when stratifying for age, T stage, and chemotherapy utilization (P < 0.001 for all). Omission of RT was also independently associated with poorer OS on multivariate analysis (P < 0.001). CONCLUSIONS: This investigation, the largest known such study to date, observed that omission of adjuvant RT for elderly women with T1-2N0 TNBC was associated with poorer OS; this was observed across a range of age groups, as well as following stratification by T stage and chemotherapy usage. Although these results do not imply causation, caution must be exercised when considering omission of adjuvant RT in node-negative TNBC patients.
Assuntos
Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/radioterapia , Distribuição por Idade , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Bases de Dados Factuais , Status Econômico/estatística & dados numéricos , Feminino , Humanos , Estimativa de Kaplan-Meier , Mastectomia Segmentar , Modelos de Riscos Proporcionais , Radioterapia Adjuvante/mortalidade , Estudos RetrospectivosRESUMO
PURPOSE: Tumor genomic testing has become widely available in many clinical settings. However, we do not yet understand how to best harness the information yielded from this testing. We retrospectively investigated the clinical courses of 24 patients who underwent tumor genomic testing to determine whether targeted therapy is associated with improved progression free survival (PFS) compared to standard therapy. METHODS: The patient population comprised metastatic breast cancer patients who underwent tumor genomic testing (testing biopsy specimens of primary or metastatic lesions for 50 commonly mutated genes) at our institution between September 1, 2010 and June 1, 2015. Through retrospective chart review, we compared PFS for those patients who received targeted therapy based on their genomic testing results, and those who did not. RESULTS: The median PFS was 5.7 months for those who received targeted therapy versus 5.4 months for those who did not (p = 0.6). There was no statistically significant difference in PFS between the two groups. CONCLUSIONS: In this relatively small group, the PFS was markedly similar between the targeted therapy and standard therapy groups. Currently, there is no clear evidence to incorporate tumor genomic testing into routine clinical practice.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Testes Genéticos/métodos , Terapia de Alvo Molecular/métodos , Mutação , Adulto , Idoso , Intervalo Livre de Doença , Feminino , Genômica/métodos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Importance: Chemotherapy may induce alopecia. Although scalp cooling devices have been used to prevent this alopecia, efficacy has not been assessed in a randomized clinical trial. Objectives: To assess whether a scalp cooling device is effective at reducing chemotherapy-induced alopecia and to assess adverse treatment effects. Design, Setting, and Participants: Multicenter randomized clinical trial of women with breast cancer undergoing chemotherapy. Patients were enrolled from December 9, 2013, to September 30, 2016. One interim analysis was planned to allow the study to stop early for efficacy. Data reported are from the interim analysis. This study was conducted at 7 sites in the United States, and 182 women with breast cancer requiring chemotherapy were enrolled and randomized. Interventions: Participants were randomized to scalp cooling (n = 119) or control (n = 63). Scalp cooling was done using a scalp cooling device. Main Outcomes and Measures: The primary efficacy end points were successful hair preservation assessed using the Common Terminology Criteria for Adverse Events version 4.0 scale (grade 0 [no hair loss] or grade 1 [<50% hair loss not requiring a wig] were considered to have hair preservation) at the end of 4 cycles of chemotherapy by a clinician unaware of treatment assignment, and device safety. Secondary end points included wig use and scores on the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30, Hospital Anxiety and Depression Scale, and a summary scale of the Body Image Scale. Results: At the time of the interim analysis, 142 participants were evaluable. The mean (SD) age of the patients was 52.6 (10.1) years; 36% (n = 51) received anthracycline-based chemotherapy and 64% (n = 91) received taxane-based chemotherapy. Successful hair preservation was found in 48 of 95 women with cooling (50.5%; 95% CI, 40.7%-60.4%) compared with 0 of 47 women in the control group (0%; 95% CI, 0%-7.6%) (success rate difference, 50.5%; 95% CI, 40.5%-60.6%). Because the 1-tailed P value from the Fisher exact test was <.001, which crossed the superiority boundary (P = .0061), the data and safety monitoring board recommended study termination on September 26, 2016. There were no statistically significant differences in changes in any of the scales of quality of life from baseline to chemotherapy cycle 4 among the scalp cooling and control groups. Only adverse events related to device use were collected; 54 adverse events were reported in the cooling group, all grades 1 and 2. There were no serious adverse device events. Conclusions and Relevance: Among women with stage I to II breast cancer receiving chemotherapy with a taxane, anthracycline, or both, those who underwent scalp cooling were significantly more likely to have less than 50% hair loss after the fourth chemotherapy cycle compared with those who received no scalp cooling. Further research is needed to assess longer-term efficacy and adverse effects. Trial Registration: clinicaltrials.gov Identifier: NCT01986140.
Assuntos
Alopecia/prevenção & controle , Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Hipotermia Induzida/instrumentação , Couro Cabeludo , Adulto , Idoso , Alopecia/induzido quimicamente , Antraciclinas/efeitos adversos , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Hipotermia Induzida/efeitos adversos , Hipotermia Induzida/métodos , Pessoa de Meia-Idade , Prevenção Primária/instrumentação , Prevenção Primária/métodos , Qualidade de Vida , Taxoides/efeitos adversosRESUMO
Atrophic vaginitis represents a major barrier to compliance with aromatase inhibitor (AI) therapy in breast cancer (BC) survivors. While local estrogen therapy is effective for postmenopausal vaginal dryness, the efficacy of such therapies has not been evaluated systematically in hormone receptor-positive (HR+) BC patients on AI therapy. Furthermore, the potential risk of breast cancer recurrence with vaginal estrogen therapy represents a long-term safety concern for the patients with HR + BC. Unfortunately, there is no standardized assay to measure very low concentrations of estradiol (E2) in these women being treated with AI therapy. This makes it difficult to evaluate even indirectly the potential risk of BC recurrence with vaginal estrogen therapy in HR + BC patients on AI therapy. In this review, we describe available assays to measure very low concentrations of E2, discuss the Food and Drug Administration-approved vaginal estrogen products on the market, and summarize published and ongoing clinical trials evaluating the safety and efficacy of vaginal estrogen in HR + BC patients on AI therapy. In the absence of any randomized controlled clinical trials, this review serves as a summary of available clinical data and ongoing studies to aid clinicians in selecting the best available option for their patients.
Assuntos
Inibidores da Aromatase/efeitos adversos , Vaginite Atrófica/tratamento farmacológico , Neoplasias da Mama/tratamento farmacológico , Estrogênios/administração & dosagem , Recidiva Local de Neoplasia/induzido quimicamente , Administração Intravaginal , Inibidores da Aromatase/uso terapêutico , Vaginite Atrófica/sangue , Vaginite Atrófica/induzido quimicamente , Neoplasias da Mama/sangue , Ensaios Clínicos como Assunto , Estradiol/sangue , Estrogênios/efeitos adversos , Feminino , Humanos , Cooperação do Paciente , Pós-Menopausa , SobreviventesRESUMO
BACKGROUND: Brain metastasis from breast cancer presents a significant threat to women's health and quality of life. Capecitabine and sunitinib have shown some activity in this setting; therefore, we conducted a single-arm phase II trial with these agents. METHODS: Patients with breast cancer and central nervous system (CNS) metastases received whole-brain radiotherapy concurrently with capecitabine (1,000 mg/m(2) per day for 14 consecutive days), followed by concomitant capecitabine (2,000 mg/m(2) per day for 2 weeks followed by a 1-week break) and sunitinib (37.5 mg daily, continuously). The primary endpoint was progression-free survival (PFS). RESULTS: Of 25 planned patients that would be required to detect a 4-month improvement (from 5 to 9 months) in median PFS with 80% power, 12 were enrolled, and the study was then closed for slow accrual. Median PFS was 4.7 months, and median overall survival was 10 months. In the CNS, 25% had progressive disease, and 83% experienced extra-CNS progression. The most common side effects were fatigue and nausea. CONCLUSION: In 12 evaluable patients studied, concurrent capecitabine and whole-brain radiation followed by capecitabine and sunitinib did not extend PFS over historical rates and was associated with significant toxicity. Our study was small and closed due to slow accrual.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/radioterapia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/radioterapia , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Neoplasias da Mama/patologia , Capecitabina , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Indóis/administração & dosagem , Pirróis/administração & dosagem , SunitinibeRESUMO
The febrile neutropenia (FN) rates reported with the docetaxel 75 mg/m(2) plus cyclophosphamide 600 mg/m(2) (TC) regimen given every 3 weeks vary from 4 to 69 % in early-stage breast cancer (ESBC) patients. This creates uncertainty as to whether patients receiving the TC regimen should also receive granulocyte colony-stimulating factor primary prophylaxis (G-CSFpp), which is recommended when chemotherapy regimens have ≥20 % FN rate. We conducted a meta-analysis of published studies to determine FN rate with the TC regimen, its dependence on patients' age, and the efficacy of G-CSFpp in reducing it in ESBC patients. We systematically searched the literature via PUBMED using the following terms: 'docetaxel', 'cyclophosphamide', 'febrile neutropenia', and 'breast cancer'. Inclusion criteria were full text peer-reviewed clinical studies in English reporting FN rates with TC regimen in relationship to G-CSFpp. Comprehensive meta-analysis software was used for all statistical analyses. Eight studies (N = 1542 patients) were included in our meta-analysis. The pooled mean FN rate was 23.2 % (95 % confidence interval (CI) 6.9-55.2 %; Q = 218.17, I (2) = 97.7). The FN risk in <65 years old patients was lower by 67.7 % compared to that in patients ≥65 years old (pooled odds ratio (OR) 0.323; 95 % CI 0.127-0.820; P = 0.017). The FN risk was reduced by 92.3 % with G-CSFpp (pooled OR 0.077; 95 % CI 0.013-0.460; P = 0.005). Our meta-analysis demonstrated that TC regimen was associated with ≥20 % FN risk, which was significantly higher in patients ≥65 years old and improved with G-CSFpp. G-CSFpp should be considered for all ESBC patients receiving TC regimen, especially those ≥65 years old.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/complicações , Neutropenia Febril/etiologia , Neutropenia Febril/prevenção & controle , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Docetaxel , Neutropenia Febril/epidemiologia , Feminino , Humanos , Estadiamento de Neoplasias , Razão de Chances , Profilaxia Pré-Exposição , Risco , Taxoides/administração & dosagemRESUMO
PURPOSE: A Phase 2 trial of stereotactic radiotherapy and in situ cytotoxic virus therapy in patients with metastatic triple-negative breast cancer (mTNBC) followed by pembrolizumab (STOMP) was designed to evaluate dual approach of enhancing single-agent immune checkpoint blockade with adenovirus-mediated expression of herpes-simplex-virus thymidine-kinase (ADV/HSV-tk) plus valacyclovir gene therapy and stereotactic body radiotherapy (SBRT) in patients with mTNBC. PATIENTS AND METHODS: In this single-arm, open-label Phase 2 trial, patients with mTNBC were treated with ADV/HSV-tk [5 × 1011 virus particles (vp)] intratumoral injection, followed by SBRT to the injected tumor site, then pembrolizumab (200 mg, every 3 weeks). The primary endpoint was clinical benefit rate [CBR; complete response (CR), partial response (PR), or stable disease (SD) ≥ 24 weeks per RECIST version1.1 at non-irradiated site]. Secondary endpoints included duration on treatment (DoT), overall survival (OS), and safety. Exploratory endpoints included immune response to treatment assessed by correlative tissue and blood-based biomarkers. RESULTS: Twenty-eight patients were enrolled and treated. CBR was seen in 6 patients (21.4%), including 2 CR (7.1%), 1 PR (3.6%), and 3 SD (10.7%). Patients with clinical benefit had durable responses, with median DoT of 9.6 months and OS of 14.7 months. The median OS was 6.6 months in the total population. The combination was well tolerated. Correlative studies with Cytometry by Time of Flight (CyTOF) and imaging mass cytometry (IMC) revealed a significant increase of CD8 T cells in responders and of myeloid cells in non-responders. CONCLUSIONS: The median OS increased by more than 2-fold in patients with clinical benefit. The therapy is a well-tolerated treatment in heavily pretreated patients with mTNBC. Early detection of increased effector and effector memory CD8 T cells and myeloids correlate with response and non-response, respectively.
Assuntos
Radiocirurgia , Neoplasias de Mama Triplo Negativas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Genética , Humanos , Inibidores de Checkpoint Imunológico , Timidina/uso terapêutico , Timidina Quinase/genética , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Valaciclovir/uso terapêuticoRESUMO
The transbilayer movement of phosphatidylserine from the inner to the outer leaflet of the membrane bilayer during platelet activation is associated with the release of procoagulant phosphatidylserine-rich small membrane vesicles called platelet-derived microvesicles. We tested the effect of lactadherin, which promotes the phagocytosis of phosphatidylserine-expressing lymphocytes and red blood cells, in the clearance of platelet microvesicles. Platelet-derived microvesicles were labeled with BODIPY-maleimide and incubated with THP-1-derived macrophages. The extent of phagocytosis was quantified by flow cytometry. Lactadherin promoted phagocytosis in a concentration-dependent manner with a half-maximal effect at approximately 5 ng/mL. Lactadherin-deficient mice had increased number of platelet-derived microvesicles in their plasma compared with their wild-type littermates (950 +/- 165 vs 4760 +/- 650; P = .02) and generated 2-fold more thrombin. In addition, splenic macrophages from lactadherin-deficient mice showed decreased capacity to phagocytose platelet-derived microvesicles. In an in vivo model of light/dye-induced endothelial injury/thrombosis in the cremasteric venules, lactadherin-deficient mice had significantly shorter time for occlusion compared with their wild-type littermate controls (5.93 +/- 0.43 minutes vs 9.80 +/- 1.14 minutes;P = .01). These studies show that lactadherin mediates the clearance of phosphatidylserine-expressing platelet-derived microvesicles from the circulation and that a defective clearance can induce a hypercoagulable state.
Assuntos
Antígenos de Superfície/fisiologia , Plaquetas/fisiologia , Endotélio Vascular/metabolismo , Trombose/metabolismo , Animais , Apoptose , Compostos de Boro , Células Cultivadas , Endotélio Vascular/citologia , Citometria de Fluxo , Humanos , Ativação de Macrófagos , Maleimidas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas do Leite , Fagocitose , Fenantrenos/farmacologia , Fosfatidilserinas/metabolismo , Ativação Plaquetária/efeitos dos fármacos , Baço/citologia , Baço/metabolismo , Trombina/metabolismoRESUMO
Anti-Yo-associated paraneoplastic cerebellar degeneration (PCD) syndrome is a very rare condition that is most commonly associated with breast and gynecologic cancers. Those cases associated with breast cancer tend to be human epidermal growth factor receptor 2 (HER2)-positive, though the reason for this correlation is unknown. Most commonly, the neurologic symptoms of the PCD syndrome predate the patient's cancer diagnosis. Thus, prompt diagnosis of PCD is essential to allow for early treatment of the neurologic symptoms and the underlying malignancy. However, the prognosis is very poor for the anti-Yo-associated paraneoplastic syndrome, since neurologic damage is usually rapid and irreversible. Further progression may be stopped with appropriate treatment of cancer, but existing neurologic deficits at the time of diagnosis are usually permanent. Steroids, plasma exchange, and rituximab are commonly used treatments, though these have had mixed to poor results.
RESUMO
INTRODUCTION: Chemotherapy eliminates most of the cancer cells except those with potential for self-renewal and tumor initiation, called cancer stem cells (CSCs). Chloroquine, through bioinformatics, was found to be a potential agent to target CSCs. We designed a phase II trial to test the efficacy and safety of chloroquine in combination with taxane or taxane-like chemotherapy agents in patients with advanced or metastatic breast cancer who are refractory to anthracycline-based chemotherapy. PATIENTS AND METHODS: Female patients ≥ 18 years of age who had received prior anthracycline chemotherapy were enrolled in this study. Chloroquine 250 mg was given daily orally with either docetaxel or paclitaxel or nab-paclitaxel or ixabepilone every 3 weeks. The maximum number of 3-week cycles allowed was 6. The primary efficacy endpoint was the objective response rate (ORR). The secondary efficacy endpoints included progression-free survival (PFS) and safety analysis. RESULTS: Thirty-eight patients were enrolled in the study, and 31 patients were evaluated for response. The median age was 54.1 years (range, 31.7-78.1 years). The ORR was 45.16% (95% confidence interval [CI], 29.2%-62.2%), which was higher than the expected ORR of 30% (P = .03). Patients were followed for a median of 25.4 months and experienced a median PFS of 12.4 months (95% CI, 4.9-24.6 months) and a median OS of 25.4 months (95% CI, 13.7-83.5 months). The combination was well-tolerated, with only 13.15% of patients experiencing grade ≥ 3 adverse events. CONCLUSION: A combination of chloroquine with taxane or taxane-like chemotherapy was efficacious in patients with locally advanced or metastatic breast cancer with prior anthracycline-based chemotherapy.
Assuntos
Antraciclinas/uso terapêutico , Antibióticos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Cloroquina/uso terapêutico , Taxoides/uso terapêutico , Adulto , Idoso , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
Triple-negative breast cancer (TNBC) patients who do not achieve pathologic complete response post neoadjuvant chemotherapy have a poor prognosis. Alteration in PI3K/mTOR plus DNA repair pathways are some of the major mechanisms of chemotherapy resistance. We designed an open-label phase II clinical trial to evaluate if the combination of everolimus (mTOR inhibitor) plus cisplatin (interferes with DNA function) will improve the rate of pathologic response, as assessed by residual cancer burden (RCB). Twenty-four Stage II/III TNBC patients with residual cancer > 1 cm post neoadjuvant anthracycline and taxane-based chemotherapy were enrolled. Patients received everolimus daily orally at 10 mg for 12 weeks and cisplatin IV at 20 mg/m2 weekly for 4 cycles (21-day cycle), until definitive surgery. The primary endpoint was the rate of RCB-0-I at the surgery. The median age of the whole cohort was 50.1 years, with 66.7% non-Hispanic Caucasians. Of the 24 patients enrolled, 22 were included in the efficacy analysis. Twenty-one patients underwent definitive surgery while one patient developed distant metastasis. Five patients had RCB-I at surgery, a response rate of 23% (5/22). Patients with germline PALB2 mutation or somatic PI3KCA mutation had a pathologic response, achieving RCB-I at the surgery. Three patients had metaplastic histology achieving RCB-I at the surgery. Estimated OS at 1 year was 100% in the RCB-I group vs. 76.5% in others, which was not statistically significant due to the small sample size. Certain cohorts including PALB2 germline mutation carrier and somatic PI3KCA mutations warrant further investigation.Trial registration: Clinicaltrials.gov identifier: NCT01931163. https://clinicaltrials.gov/ct2/show/NCT01931163 .
Assuntos
Antineoplásicos/uso terapêutico , Cisplatino/uso terapêutico , Reparo do DNA/efeitos dos fármacos , Everolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Antineoplásicos/administração & dosagem , Cisplatino/administração & dosagem , Quimioterapia Combinada , Everolimo/administração & dosagem , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Análise de Sobrevida , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/mortalidade , Sequenciamento do ExomaRESUMO
The inducible nitric oxide signaling (iNOS) pathway is associated with poor prognosis in triple-negative breast cancer (TNBC). Prior studies using in vivo models showed that inhibition of the iNOS signaling pathway using the pan-NOS inhibitor NG-monomethyl-l-arginine (L-NMMA) reduced tumor growth and enhanced survival in patients with TNBC. Here, we report a first-in-class phase 1/2 trial of L-NMMA combined with taxane for treating patients with chemorefractory, locally advanced breast cancer (LABC) or metastatic TNBC. We also examined immune cell correlates of chemotherapy response. 35 patients with metastatic TNBC were recruited: 15 in the phase 1 trial and 24 in the phase 2 trial (including 4 recommended phase 2 dose patients from the phase 1 trial). The overall response rate was 45.8% (11 of 24): 81.8% (9 of 11) for patients with LABC and 15.4% (2 of 13) for patients with metastatic TNBC. Among the patients with LABC, three patients had a pathological complete response at surgery (27.3%). Grade ≥3 toxicity was noted in 21% of patients; however, no adverse events were attributed to L-NMMA. Immune cells analyzed by CyTOF indicated that chemotherapy nonresponders showed greater expression of markers associated with M2 macrophage polarization and increased concentrations of circulating IL-6 and IL-10 cytokines. In contrast, chemotherapy responders showed an increase in CD15+ neutrophils in blood, as well as a decrease in arginase (a marker of protumor N2 neutrophils) in tumor biopsies obtained at the end of treatment. L-NMMA combined with taxane warrants further investigation in larger clinical studies of patients with breast cancer.
Assuntos
Neoplasias de Mama Triplo Negativas , Inibidores Enzimáticos/farmacologia , Humanos , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/uso terapêutico , Taxoides/farmacologia , Taxoides/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , ômega-N-Metilarginina/farmacologia , ômega-N-Metilarginina/uso terapêuticoRESUMO
This letter highlights a rare association of anti-HER2 cancer therapy with development of pulmonary arterial hypertension, based on a review of data from the FDA https://bit.ly/2X90xDu.
RESUMO
PURPOSE: Metaplastic breast cancer (MBC) is a rare, aggressive variant of breast cancer that has been associated with poor clinical outcomes, as has triple-negative breast (TNBC) cancer. Limited studies compare the clinical characteristics and prognosis of MBC to TNBC. This study uses a large, contemporary US cancer database to compare clinical characteristics and survival outcomes for patients with MBC to those with TNBC. METHODS: The National Cancer Database was queried for women with cT1-4N1-3M0 MBC or TNBC diagnosed between 2004 and 2013 and treated with definitive surgery. Chi-squared analysis was performed to determine differences between the cohorts. Kaplan-Meier curves compared overall survival (OS), and Cox regression determined patient factors associated with OS. RESULTS: Altogether, 55,847 patients met the inclusion criteria; 50,705 (90.8%) had TNBC and 5,142 (9.2%) had MBC. Most patients had no comorbid conditions (82%), N0 disease (71%), poorly differentiated histology (77%), received chemotherapy (87%), and received radiation therapy (60%). Amongst all patients, patients with TNBC disease were observed to have greater OS than those with MBC (5-year OS 72.0% vs 55.8%, pâ¯<â¯0.001). The greater observed OS for patients with TNBC persisted when controlling for stage and when comparing propensity score matched cohorts. On Cox regression, lower age, T1 status, N0 status, chemotherapy, TNBC disease, and radiation therapy (RT) were associated with improved OS. CONCLUSIONS: MBC had an association with poorer OS compared to TNBC, while RT and chemotherapy receipt were associated with improved OS for patients regardless of stage. Further studies are needed to corroborate the conclusions herein.