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BACKGROUND: The PI3K-mTOR pathway is frequently dysregulated in breast cancer. Combining an inhibitor targeting all class I PI3K isoforms and mTOR complex 1 (mTORC1)-mTOR complex 2 (mTORC2) with endocrine therapy and a CDK4/6 inhibitor might provide more effective tumour control than standard-of-care therapy. To evaluate this hypothesis, gedatolisib, a pan-PI3K-mTOR inhibitor, was assessed in a phase 1b trial combined with palbociclib and endocrine therapy in patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Results from the dose expansion portion of this trial are reported herein. METHODS: This multicentre, open-label, phase 1b study recruited female patients aged at least 18 years from 17 sites across the USA with hormone-receptor-positive, HER2-negative, advanced breast cancer and an Eastern Cooperative Oncology Group performance status of 0-1. Four patient groups were studied in the dose expansion portion of the study: treatment-naive in the advanced setting (first line; group A), progression on 1-2 lines of endocrine therapy but CDK4/6 inhibitor-naive (group B); and one or more previous lines (second-line and higher) of therapy, including a CDK4/6 inhibitor (groups C and D). Gedatolisib 180 mg was administered intravenously weekly in 28-day treatment cycles for groups A-C, and on days 1, 8, and 15 for group D. Letrozole (group A), fulvestrant (groups B-D), and palbociclib (all groups) were administered at standard doses and schedules. The primary endpoint was investigator-assessed objective response rate per RECIST version 1.1 in the evaluable analysis set. This trial is completed and registered with ClinicalTrials.gov, NCT02684032. FINDINGS: Between Dec 19, 2017, and June 19, 2019, 103 female participants were enrolled in the dose expansion groups A (n=31), B (n=13), C (n=32), and D (n=27). Median follow-up was 16·6 months (IQR 5·7-48·4) for group A, 11·0 months (7·6-16·9) for group B, 3·6 months (1·8-7·5) for group C, and 9·4 months (5·3-16·7) for group D for the primary endpoint. Gedatolisib, palbociclib, and endocrine therapy induced an objective response in 23 (85·2%; 90% CI 69·2-94·8) of 27 evaluable first-line participants (group A). In the second-line and higher setting, an objective response was observed in eight (61·5%; 90% CI 35·5-83·4) of 13 evaluable group B participants, seven (25·0%; 12·4-41·9) of 28 evaluable group C participants, and 15 (55·6%; 38·2-72·0) of 27 evaluable group D participants; this included participants with both wild-type and mutated PIK3CA tumours. The most common grade 3-4 treatment-related adverse events were neutropenia (65 [63%] of 103), stomatitis (28 [27%]), and rash (21 [20%]). Grade 3-4 hyperglycaemia was reported in six (6%) participants. 23 (22%) of 103 participants had a treatment-related serious adverse event, and there were no treatment-related deaths. Nine (9%) participants discontinued treatment because of a treatment-emergent adverse event. INTERPRETATION: Gedatolisib plus palbociclib and endocrine therapy showed a promising objective response rate compared with the published results for standard-of-care therapies and had an acceptable safety profile. FUNDING: Pfizer and Celcuity.
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Neoplasias da Mama , Morfolinas , Piperazinas , Piridinas , Triazinas , Feminino , Humanos , Adolescente , Adulto , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Intervalo Livre de Doença , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Serina-Treonina Quinases TORRESUMO
There are limited real-world comparative effectiveness data for palbociclib plus an aromatase inhibitor (AI) as a first-line (1L) treatment examining endpoints that require long term follow-up and post 1L progression. The Flatiron Health Analytic Database was used to characterize treatment and dosing patterns in patients with hormone receptor-positive/human epidermal growth factor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) receiving palbociclib plus an AI vs an AI alone in routine US clinical practice. In addition, time to chemotherapy (TTC) and real-world progression-free survival (rwPFS) when combining 1L and second-line of therapy (rwPFS2) were assessed. Of 1324 patients who received palbociclib plus an AI between February 3, 2015 and March 31, 2020, 1110 (83.8%) started palbociclib at the recommended 125 mg/day dose. After stabilized inverse probability treatment-weighting (sIPTW), median TTC in patients treated with palbociclib plus an AI and AI alone was 37.4 months (95% confidence interval [CI], 33.7-40.7) and 29.2 months (95% CI, 26.8-33.5), respectively (hazard ratio [HR] = 0.77 [95% CI, 0.69-0.86], P < .0001); median rwPFS2 was 32.6 months (95% CI, 29.4-35.2) and 20.7 months (95% CI, 18.9-22.6), respectively (HR = 0.62 [95% CI, 0.54-0.70], P < .0001). Sensitivity analyses with propensity score matching showed similar results to sIPTW analyses. Results from this large real-world study examining additional effectiveness outcomes beyond 1L rwPFS and overall survival support the use of palbociclib plus an AI as a 1L treatment for patients with HR+/HER2- mBC.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Inibidores da Aromatase/uso terapêutico , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica , Estudos RetrospectivosRESUMO
BACKGROUND: Hormone receptor (HR)-positive, HER2-negative metastatic invasive lobular breast cancer (mILC) is distinct from invasive ductal cancer (IDC) in clinicopathologic and molecular characteristics, impacting its response to systemic therapy. While endocrine therapy (ET) combined with targeted therapies has shown efficacy in ET-sensitive mILC, data on chemotherapy in ET-refractory mILC remain limited. We investigated the efficacy of single-agent capecitabine (CAP) versus taxanes (TAX) in ET-refractory HR+ HER2-negative patients with mILC. MATERIALS AND METHODS: Using data from the MD Anderson prospectively collected breast cancer database, we identified patients with HR+ HER2-negative mILC who received prior ET and first-time chemotherapy in the metastatic setting. We compared outcomes between 173 CAP-treated and 96 TAX-treated patients. RESULTS: CAP-treated patients had significantly better median progression-free survival (PFS) than TAX-treated patients (8.8 vs 5.0 months, HR 0.63, Pâ <â .001). Overall survival (OS) did not differ significantly between the groups (42.7 vs 36.6 months for CAP vs TAX, respectively, HR 0.84, Pâ =â .241). Multivariate analyses for PFS and OS revealed better outcomes in subjects with fewer metastatic sites and those exposed to more lines of ET. Additionally, Black patients showed worse OS outcomes compared to White patients (HR 2.46; Pâ =â .001). CONCLUSION: In ET-refractory HR+ HER2-negative mILC, single-agent CAP demonstrated superior PFS compared to TAX. Our findings highlight the potential benefit of CAP in this patient subset, warranting further investigation through prospective trials.
Assuntos
Neoplasias da Mama , Carcinoma Lobular , Humanos , Feminino , Carcinoma Lobular/patologia , Estudos Prospectivos , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapêutico , Neoplasias da Mama/patologia , Capecitabina/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
PURPOSE: Many stage III inflammatory breast cancer (IBC) patients experience a sufficient response to first-line (1L) neoadjuvant chemotherapy (NAC) to allow surgery, while some require additional NAC. We evaluated the pathologic complete response (pCR), breast cancer-free survival (BCFS) and overall survival (OS) among patients requiring 1 vs. 2-3 lines (L) of NAC prior to surgery. METHODS: Stage III IBC patients from 2 institutions who received 1L or 2-3L of NAC prior to surgery were identified. Hormone receptor and HER2 status, grade, and pCR were evaluated. BCFS and OS were evaluated by the Kaplan-Meier method. Multivariable Cox models were utilized to estimate the hazard ratio (HR). RESULTS: 808 eligible patients (1997-2020) were identified (median age 51 years, median follow-up 69 months). 733 (91%) had 1L and 75 (9%) had 2-3L of NAC. Grade III, triple-negative and HER2-positive disease were more prevalent in 2-3L patients. 178 (24%) 1L and 14 (19%) 2-3L patients had pCR. 376 1L patients and 41 2-3L patients had recurrences. The 5-year BCFS was worse for the 2-3L group (33 vs. 46%, HR = 1.37; 95% CI 0.99-1.91). However, in 192 patients with a pCR, BCFS was similar (76 vs. 83% in 1L vs. 2-3L, respectively). There were 308 deaths (276 among 1L and 32 among 2-3L patients). The 5-year OS in 1L vs. 2-3L was 60 vs. 53% (HR = 1.32, 95% CI 0.91-1.93). CONCLUSIONS: Among stage III IBC patients, pCR rates were similar, irrespective of the NAC lines number, and BCFS and OS were comparable with pCR after 1L and 2-3L.
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Neoplasias da Mama , Neoplasias Inflamatórias Mamárias , Humanos , Pessoa de Meia-Idade , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Terapia Neoadjuvante , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Estadiamento de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia Adjuvante , Receptor ErbB-2/genéticaRESUMO
BACKGROUND: Inflammatory breast cancer (IBC) is rare and biologically aggressive. We sought to assess diagnostic and management strategies among the American Society of Breast Surgeons (ASBrS) membership. PATIENTS AND METHODS: An anonymous survey was distributed to ASBrS members from March to May 2023. The survey included questions about respondents' demographics and information related to stage III and IV IBC management. Agreement was defined as a shared response by >80% of respondents. In areas of disagreement, responses were stratified by years in practice, fellowship training, and annual IBC patient volume. RESULTS: The survey was administered to 2337 members with 399 (17.1%) completing all questions and defining the study cohort. Distribution of years in practice was 26.0% 0-10 years, 26.6% 11-20 years and 47.4% > 20 years. Overall, 51.2% reported surgical oncology or breast fellowship training, 69.2% maintain a breast-only practice, and 73.5% treat < 5 IBC cases/year. Agreement was identified in diagnostic imaging, trimodal therapy, and mastectomy with wide skin excision for stage III IBC. Lack of agreement was identified in surgical management of the axilla; respondents with < 10 years in practice or fellowship training were more likely to perform axillary dissection for cN0-N2 stage III IBC. Locoregional management of stage IV IBC was variable. CONCLUSIONS: Among ASBrS members, there is consensus in diagnostic evaluation, treatment sequencing and surgical approach to the breast in stage III IBC. Differences exist in surgical management of the cN0-2 axilla with uptake of de-escalation strategies. Clinical trials are needed to evaluate oncologic safety of de-escalation in this high-risk population.
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WHAT IS THIS SUMMARY ABOUT?: This summary describes an article published in the medical journal Frontiers in Oncology in September 2023. The article reports results from a study that looked at breast cancer treatments for older patients aged 75 years or older. The study focused on a type of cancer called HR+/HER2- metastatic breast cancer. HR+/HER2- stands for hormone receptorpositive/human epidermal growth factor receptor 2-negative. This study evaluated whether older patients with this type of cancer benefited from the combination of two medicines - palbociclib and an aromatase inhibitor - compared with taking an aromatase inhibitor alone. HOW WAS THE STUDY IN THIS SUMMARY CARRIED OUT?: The Flatiron database contains medical records for people with cancer in the US. This study used deidentified health care information from this database. 'Deidentified' means that all information that could identify an individual was removed to protect individuals' privacy. People in this study received treatment in routine care and not in a clinical trial. WHAT DO THE RESULTS MEAN?: Older patients who took palbociclib plus an aromatase inhibitor lived longer than those who took an aromatase inhibitor alone. Older patients who took palbociclib plus an aromatase inhibitor also lived longer without their cancer getting worse and started chemotherapy later than those who took an aromatase inhibitor alone. These results support using palbociclib plus an aromatase inhibitor as the first treatment for patients aged 75 years or older with HR+/HER2- metastatic breast cancer.
This study evaluated outcomes in elderly patients with metastatic breast cancer treated in routine care. Overall, patients who took palbociclib plus an aromatase inhibitor (AI) lived longer, and lived longer without their cancer getting worse, than those who took an AI alone.
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Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores da Aromatase , Neoplasias da Mama , Piperazinas , Piridinas , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Feminino , Inibidores da Aromatase/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Piridinas/uso terapêutico , Piridinas/administração & dosagem , Idoso , Piperazinas/uso terapêutico , Piperazinas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso de 80 Anos ou mais , Resultado do Tratamento , Metástase Neoplásica , Receptor ErbB-2/metabolismoRESUMO
WHAT IS THIS SUMMARY ABOUT?: This summary is about a study that was published in the medical journal The Oncologist in July 2023. The combination of palbociclib with an aromatase inhibitor (AI) was approved by the FDA in 2015 as a treatment for people with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (MBC). However, the effectiveness of palbociclib in African-Americans with MBC is not well studied. The goal of this study was to find out whether adding palbociclib to an AI helped African-Americans with HR+/HER2- MBC live longer. WHAT ARE THE KEY TAKEAWAYS?: This study used de-identified medical information from the Flatiron Database. This database contains healthcare information on people with cancer treated by doctors in the United States but personal information is removed to maintain privacy. Medical information for people who received certain treatments in routine clinical practice or real-world setting was included in the study.This study showed that in the real-world setting, African-Americans with HR+/HER2- MBC lived longer when receiving palbociclib with an AI than with an AI alone. Also, the study showed that African-Americans treated with palbociclib plus an AI lived longer without their cancer getting worse than those treated with an AI alone. WHAT WAS THE MAIN CONCLUSION REPORTED BY THE RESEARCHERS?: These results support the use of palbociclib with an AI as a first treatment for African-Americans with HR+/HER2- MBC.Clinical Trial Registration: NCT05361655 (ClinicalTrials.gov).
Effectiveness of palbociclib plus an aromatase inhibitor in African Americans with metastatic breast cancer in routine clinical practice: a plain language summary.
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Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores da Aromatase , Negro ou Afro-Americano , Neoplasias da Mama , Bases de Dados Factuais , Piperazinas , Piridinas , Humanos , Piperazinas/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Inibidores da Aromatase/uso terapêutico , Piridinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Negro ou Afro-Americano/estatística & dados numéricos , Pessoa de Meia-Idade , Metástase Neoplásica , Idoso , Receptor ErbB-2/metabolismo , Adulto , Estados UnidosRESUMO
BACKGROUND: Disparities in survival and clinical outcomes between African American and White patients with breast cancer (BC) are well documented, but African American patients have not been well represented in randomized clinical trials of CDK4/6 inhibitors. Real-world studies can provide evidence for effective treatment strategies for underreported patient populations. PATIENTS AND METHODS: This retrospective analysis of African American patients with HR+/HER2- metastatic breast cancer (mBC) from the Flatiron Health longitudinal database evaluated treatments for patients with BC in routine clinical practice in the US. Patients initiated first-line therapy with palbociclib plus an aromatase inhibitor (AI) or AI alone between February 2015 and March 2020. Outcomes assessed included overall survival (OS) and real-world progression-free survival (rwPFS) until September 2020. RESULTS: Of 270 eligible patients, 127 (median age 64 years) were treated with palbociclib + AI, and 143 (median age 68 years) were treated with an AI. Median follow-up was 24.0 months for palbociclib + AI and 18.2 months for AI-treated patients. Median OS was not reached (NR; 95% CI, 38.2-NR) in the palbociclib + AI group versus 28.2 months (95% CI, 19.2-52.8) in the AI group (adjusted HR, 0.56; 95% CI, 0.36-0.89; Pâ =â .013). Median rwPFS was 18.0 months (95% CI, 12.4-26.7) in the palbociclib + AI group and 10.5 months (95% CI, 7.0-13.4) in the AI group (adjusted HR, 0.74; 95% CI, 0.47-1.17; Pâ =â .199). CONCLUSION: This comparative analysis of palbociclib + AI versus AI alone indicates that palbociclib combined with endocrine therapy in the first line is associated with improved effectiveness for African American patients with HR+/HER2- mBC in real-world settings. TRIAL NUMBER: NCT05361655.
Assuntos
Neoplasias da Mama , Idoso , Feminino , Humanos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/efeitos adversos , Inibidores da Aromatase/uso terapêutico , Negro ou Afro-Americano , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/etnologia , Neoplasias da Mama/patologia , Receptor ErbB-2/uso terapêutico , Estudos RetrospectivosRESUMO
PURPOSE: Neoadjuvant anti-PD-(L)1 therapy improves the pathological complete response (pCR) rate in unselected triple-negative breast cancer (TNBC). Given the potential for long-term morbidity from immune-related adverse events (irAEs), optimizing the risk-benefit ratio for these agents in the curative neoadjuvant setting is important. Suboptimal clinical response to initial neoadjuvant therapy (NAT) is associated with low rates of pCR (2-5%) and may define a patient selection strategy for neoadjuvant immune checkpoint blockade. We conducted a single-arm phase II study of atezolizumab and nab-paclitaxel as the second phase of NAT in patients with doxorubicin and cyclophosphamide (AC)-resistant TNBC (NCT02530489). METHODS: Patients with stage I-III, AC-resistant TNBC, defined as disease progression or a < 80% reduction in tumor volume after 4 cycles of AC, were eligible. Patients received atezolizumab (1200 mg IV, Q3weeks × 4) and nab-paclitaxel (100 mg/m2 IV,Q1 week × 12) as the second phase of NAT before undergoing surgery followed by adjuvant atezolizumab (1200 mg IV, Q3 weeks, × 4). A two-stage Gehan-type design was employed to detect an improvement in pCR/residual cancer burden class I (RCB-I) rate from 5 to 20%. RESULTS: From 2/15/2016 through 1/29/2021, 37 patients with AC-resistant TNBC were enrolled. The pCR/RCB-I rate was 46%. No new safety signals were observed. Seven patients (19%) discontinued atezolizumab due to irAEs. CONCLUSION: This study met its primary endpoint, demonstrating a promising signal of activity in this high-risk population (pCR/RCB-I = 46% vs 5% in historical controls), suggesting that a response-adapted approach to the utilization of neoadjuvant immunotherapy should be considered for further evaluation in a randomized clinical trial.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Antraciclinas/uso terapêutico , Neoplasias de Mama Triplo Negativas/patologia , Terapia Neoadjuvante , Neoplasias da Mama/tratamento farmacológico , Paclitaxel/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
WHAT IS THIS SUMMARY ABOUT?: This is a summary of an article about a study called "P-REALITY X" that was published in the medical journal npj Breast Cancer in October 2022. "P-REALITY X" stands for Palbociclib REAl-world first-LIne comparaTive effectiveness studY eXtended. This study used information from a database to look at whether adding a second treatment (palbociclib) to an aromatase inhibitor (AI) helped people with a certain type of breast cancer to live longer. The type of breast cancer is metastatic hormone receptor-positive/human epidermal growth factor-negative breast cancer, also called HR-positive (or HR+)/HER2-negative (or HER2-) breast cancer. The study used information from the Flatiron Database. This database contains unidentified health care information collected from people seen by doctors in the USA. Only data from people who did not participate in a clinical trial were used. When people are treated outside of a clinical trial, this is called the real-world setting, or routine clinical practice. In clinical trials, people lived longer without their disease worsening if they were treated with palbociclib plus an AI versus being treated with an AI only. Based on the results of clinical trials, treatment with palbociclib plus an AI is already approved and recommended for people with HR+/HER2- breast cancer. This study looked at whether people lived longer if they were treated with palbociclib plus an AI versus being treated with an AI only in routine clinical practice as well. WHAT WERE THE RESULTS?: This study showed that, in routine clinical practice, people treated with the medicine palbociclib plus an AI lived longer than people treated with only an AI. WHAT DO THE RESULTS MEAN?: These results support the continued use of palbociclib plus an AI as the standard first medicine to be given to people with metastatic HR+/HER2- breast cancer. Clinical Trial Registration: NCT05361655 (ClinicalTrials.gov).
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Inibidores da Aromatase/uso terapêutico , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
Cyclin-dependent-kinase-4/6 inhibitor (CDK4/6i) plus endocrine therapy (ET) is standard of care for patients with advanced hormone receptor (HR)-positive, HER2-negative breast cancer (BC). The Breast Medical Oncology database at MD Anderson Cancer Center (MDACC) was analyzed to assess effectiveness of the CDK4/6i palbociclib plus ET compared to ET alone. From a total of 5402 advanced HR+ HER2- BC patients referred to MDACC between 1997 and 2020, we identified eligible patients who received palbociclib in combination with first-line (n = 778) and second-line (n = 410) ET. We further identified "control" patients who received ET alone in the first-line (n = 2452) and second-line (n = 1183) settings. Propensity score matching analysis was conducted to balance baseline demographic and clinical characteristics between palbociclib and control cohorts to assess the effect of palbociclib treatment on progression-free survival (PFS) and overall survival (OS). For propensity-matched-cohort in the first-line setting (n = 708), palbociclib group had significantly longer median PFS (17.4 vs 11.1 months; P < .0001) compared to controls. Median OS (44.3 vs 40.2 months) did not show a statistically significant benefit in the first line setting. However, in the second-line setting, with 380 propensity-matched-cohort, the palbociclib group had significantly longer PFS (10 vs 5 months, P < .0001) as well as OS (33 vs 24 months; P < .022), compared to controls. We conclude that in this single center analysis of a large cohort of metastatic HR+ HER2- BC patients, palbociclib in combination with ET was associated with improved PFS in both first-line and second-line settings and OS in the second-line setting compared to ET alone cohort.
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Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Piperazinas , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas , Receptor ErbB-2 , Receptores de EstrogênioRESUMO
Invasive lobular carcinoma (ILC) is the second most common histologic subtype of breast cancer after invasive ductal carcinoma (IDC), accounting for 10-15% of all breast cancer cases. Although most ILCs are of the luminal A intrinsic subtype, with favorable prognostic features, conflicting literature data are available on their outcomes compared to IDC with reports suggesting a higher risk of distant recurrence after 10 years. Historically, studies have combined ILC and IDC, with outcomes largely driven by the behavior of IDC given that it represents 90% of breast cancers. However, over the past 5 years, reports of several studies aimed at understanding ILC at the clinical, cellular, and molecular levels have been published, showing that IDC and ILC are distinct entities. In this review, we highlight the unique characteristics of ILC and describe the need for dedicated ILC clinical trials.
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Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Lobular , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/terapia , Feminino , Humanos , PrognósticoRESUMO
BACKGROUND: Inflammatory breast cancer (IBC) is a rare and aggressive subtype of breast cancer characterized by rapid progression and early metastasis, often with advanced nodal locations, including the supraclavicular (SCV) nodal basin. Previously considered M1 disease, ipsilateral clinical supraclavicular node involvement (N3c) disease is now considered locally advanced disease and warrants treatment with intent to cure. The objective of this study was to evaluate the long-term outcomes of patients with IBC and N3c disease. PATIENTS AND METHODS: This study was conducted using a prospectively collected database of all patients with IBC treated at a dedicated cancer center from 2007 to 2019. Surgical patients with SCV nodal involvement and complete follow-up were identified. Our primary outcome was 5-year overall survival (OS). Multivariate Cox proportional hazards models were used to determine predictors for survival. Event-free survival (EFS) and OS were calculated using the Kaplan-Meier method. RESULTS: There were 70 patients who met inclusion criteria. All patients underwent comprehensive trimodality therapy. The majority of patients had complete (66.2%) radiologic response in the SCV nodal basins following neoadjuvant therapy. Six patients (8.6%) had a locoregional recurrence, with two (2.9%) occurring in the supraclavicular fossa. The 5-year OS was 60.2% [95% confidence interval (CI) 47.7-72.7%]. Increasing age (hazard ratio 2.7; p = 0.03) and triple-negative subtype (hazard ratio 4.9; p = 0.03) were associated with poor OS. The 5-year EFS was 56.1% (95% CI 40.9-68.8%). The presence of more than ten positive axillary nodes on final surgical pathology (hazard ratio 5.5; p = 0.01) predicted poor EFS. CONCLUSIONS: With comprehensive trimodality therapy and multidisciplinary team approach, patients with IBC with supraclavicular nodal involvement experience excellent locoregional control and favorable survival.
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Neoplasias da Mama , Neoplasias Inflamatórias Mamárias , Neoplasias da Mama/cirurgia , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/patologia , Neoplasias Inflamatórias Mamárias/terapia , Linfonodos/patologia , Terapia Neoadjuvante , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/terapia , Modelos de Riscos Proporcionais , Estudos RetrospectivosRESUMO
BACKGROUND: Findings from randomized clinical trials may have limited generalizability to patients treated in routine clinical practice. This study examined the effectiveness of first-line palbociclib plus letrozole versus letrozole alone on survival outcomes in patients with hormone receptor-positive (HR+)/human epidermal growth factor receptor-negative (HER2-) metastatic breast cancer (MBC) treated in routine clinical practice in the USA. PATIENTS AND METHODS: This was a retrospective observational analysis of electronic health records within the Flatiron Health Analytic Database. A total of 1430 patients with ≥ 3 months of follow-up received palbociclib plus letrozole or letrozole alone in the first-line setting between February 3, 2015, and February 28, 2019. Stabilized inverse probability treatment weighting (sIPTW) was used to balance baseline demographic and clinical characteristics. Real-world progression-free survival (rwPFS) and overall survival (OS) were analyzed. RESULTS: After sIPTW adjustment, median follow-up was 24.2 months (interquartile range [IQR], 14.2-34.9) in the palbociclib group and 23.3 months (IQR, 12.7-34.3) in those taking letrozole alone. Palbociclib combination treatment was associated with significantly longer median rwPFS compared to letrozole alone (20.0 vs 11.9 months; hazard ratio [HR], 0.58; 95% CI, 0.49-0.69; P < 0.0001). Median OS was not reached in the palbociclib group and was 43.1 months with letrozole alone (HR, 0.66; 95% CI, 0.53-0.82; P = 0.0002). The 2-year OS rate was 78.3% in the palbociclib group and 68.0% with letrozole alone. A propensity score matching analysis showed similar results. CONCLUSIONS: In this "real-world" population of patients with HR+/HER2- MBC, palbociclib in combination with endocrine therapy was associated with improved survival outcomes compared with patients treated with letrozole alone in the first-line setting. TRIAL REGISTRATION: Clinicaltrials.gov; NCT04176354.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Letrozol/uso terapêutico , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Idoso , Inibidores da Aromatase/uso terapêutico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/deficiência , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: Poly(ADP-ribose) polymerase inhibitors (PARPis) are U.S. Food and Drug Administration (FDA) approved for treatment of BRCA-mutated metastatic breast cancer. Furthermore, the BROCADE studies demonstrated benefit of adding an oral PARPi, veliparib, to carboplatin and paclitaxel in patients with metastatic breast cancer harboring BRCA mutation. Given multiple possible dosing schedules and the potential benefit of this regimen for patients with defective DNA repair beyond BRCA, we sought to find the recommended phase II dose (RP2D) and schedule of veliparib in combination with carboplatin in patients with advanced breast cancer, either triple-negative (TNBC) or hormone receptor (HR)-positive, human epidermal growth receptor 2 (HER2) negative with defective Fanconi anemia (FA) DNA-repair pathway based on FA triple staining immunofluorescence assay. MATERIALS AND METHODS: Patients received escalating doses of veliparib on a 7-, 14-, or 21-day schedule with carboplatin every 3 weeks. Patients underwent [18]fluoro-3'-deoxythymidine (18 FLT) positron emission tomography (PET) imaging. RESULTS: Forty-four patients (39 TNBC, 5 HR positive/HER2 negative with a defective FA pathway) received a median of 5 cycles (range 1-36). Observed dose-limiting toxicities were grade (G) 4 thrombocytopenia (n = 4), G4 neutropenia (n = 1), and G3 akathisia (n = 1). Common grade 3-4 toxicities included thrombocytopenia, lymphopenia, neutropenia, anemia, and fatigue. Of the 43 patients evaluable for response, 18.6% achieved partial response and 48.8% had stable disease. Median progression-free survival was 18.3 weeks. RP2D of veliparib was established at 250 mg twice daily on days 1-21 along with carboplatin at area under the curve 5. Patients with partial response had a significant drop in maximum standard uptake value (SUVmax ) of target lesions between baseline and early in cycle 1 based on 18 FLT-PET (day 7-21; ptrend = .006). CONCLUSION: The combination of continuous dosing of veliparib and every-3-week carboplatin demonstrated activity and an acceptable toxicity profile. Decrease in SUVmax on 18 FLT-PET scan during the first cycle of this therapy can identify patients who are likely to have a response. IMPLICATIONS FOR PRACTICE: The BROCADE studies suggest that breast cancer patients with BRCA mutation benefit from addition of veliparib to carboplatin plus paclitaxel. This study demonstrates that a higher dose of veliparib is tolerable and active in combination with carboplatin alone. With growing interest in imaging-based early response assessment, the authors demonstrate that decrease in [18]fluoro-3'-deoxythymidine positron emission tomography (FLT-PET) SUVmax during cycle 1 of therapy is associated with response. Collectively, this study established a safety profile of veliparib and carboplatin in advanced breast cancer while also providing additional data on the potential for FLT-PET imaging modality in monitoring therapy response.
Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis , Biomarcadores , Neoplasias da Mama/tratamento farmacológico , Carboplatina/uso terapêutico , Feminino , Humanos , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: We translated a multigene expression index to predict sensitivity to endocrine therapy for Stage II-III breast cancer (SET2,3) to hybridization-based expression assays of formalin-fixed paraffin-embedded (FFPE) tissue sections. Here we report the technical validity with FFPE samples, including preanalytical and analytical performance. METHODS: We calibrated SET2,3 from microarrays (Affymetrix U133A) of frozen samples to hybridization-based assays of FFPE tissue, using bead-based QuantiGene Plex (QGP) and slide-based NanoString (NS). The following preanalytical and analytical conditions were tested in controlled studies: replicates within and between frozen and fixed samples, age of paraffin blocks, homogenization of fixed sections versus extracted RNA, core biopsy versus surgically resected tumor, technical replicates, precision over 20 weeks, limiting dilution, linear range, and analytical sensitivity. Lin's concordance correlation coefficient (CCC) was used to measure concordance between measurements. RESULTS: SET2,3 index was calibrated to use with QGP (CCC 0.94) and NS (CCC 0.93) technical platforms, and was validated in two cohorts of older fixed samples using QGP (CCC 0.72, 0.85) and NS (CCC 0.78, 0.78). QGP assay was concordant using direct homogenization of fixed sections versus purified RNA (CCC 0.97) and between core and surgical sample types (CCC 0.90), with 100% accuracy in technical replicates, 1-9% coefficient of variation over 20 weekly tests, linear range 3.0-11.5 (log2 counts), and analytical sensitivity ≥2.0 (log2 counts). CONCLUSIONS: Measurement of the novel SET2,3 assay was technically valid from fixed tumor sections of biopsy or resection samples using simple, inexpensive, hybridization methods, without the need for RNA purification.
Assuntos
Neoplasias da Mama/genética , Perfilação da Expressão Gênica/estatística & dados numéricos , Análise de Sequência com Séries de Oligonucleotídeos/estatística & dados numéricos , RNA Mensageiro/análise , Aurora Quinase A/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Estudos de Coortes , Receptor alfa de Estrogênio/genética , Estrogênios/uso terapêutico , Humanos , Inclusão em Parafina , Receptor ErbB-2/genética , Receptores de Progesterona/genética , Reprodutibilidade dos Testes , Fixação de TecidosRESUMO
Upregulation of Notch pathway is associated with poor prognosis in breast cancer. We present the results of a phase I study of an oral selective gamma secretase (GS) inhibitor (critical to Notch signaling), RO4929097 in combination with neoadjuvant chemotherapy for operable triple negative breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) of RO4929097. Secondary objectives were to determine real-time pharmacokinetics of RO4929097 and paclitaxel, safety and pathologic (pCR) complete response to study treatment. Eligible patients, initiated carboplatin at AUC 6 administered intravenously (IV) on day 1, weekly paclitaxel at 80 mg/m2 IV and RO4929097 10 mg daily given orally (PO) on days 1-3, 8-10 and 15-17 for six 21-day cycles. RO4929097 was escalated in 10 mg increments using the 3 + 3 dose escalation design. Two DLTs were observed in 14 patients - Grade (G) 4 thrombocytopenia in dose level 1 (10 mg) and G3 hypertension in dose level 2 (20 mg). Protocol-defined MTD was not determined due to discontinuation of RO4929097 development. However, 4 of 5 patients enrolled to 20 mg dose of RO4929097 required dose reduction to 10 mg due to toxicities (including neutropenia, thrombocytopenia and hypertension) occurring during and beyond the DLT observation period. Thus, 10 mg would have been the likely dose level for further development. G3 or higher hematologic toxicities included neutropenia (N = 8, 57%) and thrombocytopenia (N = 5, 36%) patients. Six (43%) patients had G2-3 neuropathy requiring paclitaxel dose reduction. No signs of drug-drug interaction between paclitaxel and RO4929097 were evident. Five patients (36%) had pCR.
Assuntos
Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzazepinas/uso terapêutico , Carboplatina/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Administração Oral , Adulto , Idoso , Antineoplásicos/efeitos adversos , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Benzazepinas/efeitos adversos , Benzazepinas/sangue , Benzazepinas/farmacocinética , Carboplatina/efeitos adversos , Feminino , Humanos , Infusões Intravenosas , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/efeitos adversos , Paclitaxel/sangue , Paclitaxel/farmacocinética , Resultado do TratamentoRESUMO
BACKGROUND: While combinations of immune checkpoint (ICP) inhibitors and neo-adjuvant chemotherapy (NAC) have begun testing in patients with breast cancer (BC), the effects of chemotherapy on ICP expression in circulating T cells and within the tumor microenvironment are still unclear. This information could help with the design of future clinical trials by permitting the selection of the most appropriate ICP inhibitors for incorporation into NAC. METHODS: Peripheral blood samples and/or tumor specimens before and after NAC were obtained from 24 women with operable BC. The expression of CTLA4, PD-1, Lag3, OX40, and Tim3 on circulating T lymphocytes before and at the end of NAC were measured using flow cytometry. Furthermore, using multi-color immunohistochemistry (IHC), the expression of immune checkpoint molecules by stromal tumor-infiltrating lymphocytes (TILs), CD8+ T cells, and tumor cells was determined before and after NAC. Differences in the percentage of CD4+ and CD8+ T cells expressing various checkpoint receptors were determined by a paired Student's t-test. RESULTS: This analysis showed decreased ICP expression by circulating CD4+ T cells after NAC, including significant decreases in CTLA4, Lag3, OX40, and PD-1 (all p values < 0.01). In comparison, circulating CD8+ T cells showed a significant increase in CTLA4, Lag3, and OX40 (all p values < 0.01). Within tumor samples, TILs, CD8+ T cells, and PD-L1/PD-1 expression decreased after NAC. Additionally, fewer tumor specimens were considered to be PD-L1/PD-1 positive post-NAC as compared to pre-NAC biopsy samples using a cutoff of 1% expression. CONCLUSIONS: This work revealed that NAC treatment can substantially downregulate CD4+ and upregulate CD8+ T cell ICP expression as well as deplete the amount of TILs and CD8+ T cells found in breast tumor samples. These findings provide a starting point to study the biological significance of these changes in BC patients. TRIAL REGISTRATION: NCT04022616.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/metabolismo , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Terapia Neoadjuvante/métodos , Receptor de Morte Celular Programada 1/metabolismo , Adulto , Idoso , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/sangue , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/imunologia , Quimioterapia Adjuvante , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Microambiente TumoralRESUMO
BACKGROUND: The purpose of this study was to determine the prognostic role of hormone receptor (HR) on inflammatory breast cancer (IBC) to elucidate its aggressive biological behavior. METHODS: We evaluated the expression of estrogen receptor (ER) and progesterone receptor (PR) by immunohistochemical staining and determined the predictive and prognostic role of HR expression on 189 patients with HR+/HER2- IBC and 677 patients with HR+/HER2- stage III non-IBC. Furthermore, we performed gene expression (GE) analyses on 137 patients with HR+/HER2- IBC and 252 patients with HR+/HER2- non-IBC to detect genes that are specifically overexpressed in IBC. RESULTS: The expression of ER% was significantly associated with longer distant disease-free survival and overall survival. However, there was no significant relationship between ER% and neoadjuvant chemotherapy outcome. In the GE study, 84 genes were identified as significantly distinguishing HR+ IBC from non-IBC. Among the top 15 canonical pathways expressed in IBC, the ERK/MAPK, PDGF, insulin receptor, and IL-7 signaling pathways were associated with the ER signaling pathway. Upregulation of the MYC gene was observed in three of these four pathways. Furthermore, HR+/HER2- IBC had significantly higher MYC amplification, and the genetic alteration was associated with poor survival outcome. CONCLUSIONS: Higher ER expression was significantly associated with improved survival in both HR+/HER2- IBC and HR+/HER2- stage III non-IBC patients. HR+/HER2- IBC had several activated pathways with MYC upregulation, and the genetic alteration was associated with poor survival outcome. The results indicate that MYC may be a key gene for understanding the biology of HR+/HER2- IBC.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Inflamatórias Mamárias/patologia , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Quimioterapia Adjuvante , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Neoplasias Inflamatórias Mamárias/tratamento farmacológico , Neoplasias Inflamatórias Mamárias/genética , Neoplasias Inflamatórias Mamárias/metabolismo , Pessoa de Meia-Idade , Terapia Neoadjuvante , Prognóstico , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida , Adulto JovemRESUMO
Germline variations in genes coding for proteins involved in the oxidative stress and DNA repair greatly influence drug response and toxicity. Because BRCA1 and BRCA2 proteins play a role in DNA damage repair, we postulated that taxane-related toxicity is potentially higher and clinical outcome in different in patients with BRCA pathogenic variants (PV). Seven hundred nineteen women who underwent BRCA genetic testing and were treated with taxane-containing chemotherapy for early-stage breast cancer between 1997 and 2018 were included in the study. Patients with BRCA variants of uncertain significance were excluded. The Kaplan-Meier product-limit method was used to estimate recurrence-free survival (RFS) and overall survival (OS) rates. Logistic regression models were used to assess the association between chemotherapy toxicity and factors of interest. Cox regression models were used to assess the association between RFS and OS and factors of interest. Ninety-four (13%) and 54 (7%) patients had BRCA1 and BRCA2-PVs, respectively. While anemia (P = .0025) and leukopenia (P = .001) were more frequently seen in BRCA noncarriers, there was no difference in regards to peripheral neuropathy or other toxicities between the groups. Increasing doses of taxane were associated with increased risk of neutropenia, stomatitis, nausea, vomiting, acne/rash, and peripheral neuropathy across all groups. In a multivariate logistic regression model, BRCA2 status remained as an independent significant predictor for decreased hematologic toxicity (HR: 0.36; 95% CI: 0.20-0.67; P = .001) and increased gastrointestinal toxicity (HR: 1.93; 95% CI: 1.02-3.67; P = .04). Being overweight, obese and African-American race were significant predictors for peripheral neuropathy (P = .04; P = .03; P = .06, respectively). Total taxane dose received did not have any impact on survival outcomes. Our study demonstrates that taxane-containing chemotherapy regimens do not increase risk of peripheral neuropathy or hematologic toxicity in patients with BRCA PVs. The mechanisms for this finding need to be further investigated as it may provide an opportunity to combine taxanes with other agents, such as platinum salts or PARP inhibitors, with less anticipated toxicity.