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Metastatic breast cancer (mBC) remains an incurable disease, and most patients will experience disease progression during their treatment course. Although endocrine therapy remains the mainstay of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative mBC, significant progress has been and continues to be made in the treatment of this BC subtype. The discovery of molecular markers, mutations in key cellular pathways, and genomic signatures have led to the development of novel and targeted agents, such as antibody-drug conjugates, oral selective estrogen receptor downregulators, and inhibitors of the PI3K/AKT/mTOR pathway. This has resulted in significant improvements in the survival and quality of life of patients. With the increasing number of treatment options for patients, appropriate drug sequencing remains a challenge. Treatment discussions should involve patient-physician shared decision making, with consideration of genomic data, previous lines of therapy, side effect profiles, and clinical trial enrollment.
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Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget's disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of systemic therapy (preoperative and adjuvant) options for nonmetastatic breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.
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Neoplasias da Mama , Humanos , Neoplasias da Mama/terapia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Feminino , Oncologia/normas , Oncologia/métodos , Terapia Combinada/normasRESUMO
BACKGROUND: We previously reported our phase Ib trial, testing the safety, tolerability, and efficacy of T-DM1 + neratinib in HER2-positive metastatic breast cancer patients. Patients with ERBB2 amplification in ctDNA had deeper and more durable responses. This study extends these observations with in-depth analysis of molecular markers and mechanisms of resistance in additional patients. METHODS: Forty-nine HER2-positive patients (determined locally) who progressed on-treatment with trastuzumab + pertuzumab were enrolled in this phase Ib/II study. Mutations and HER2 amplifications were assessed in ctDNA before (C1D1) and on-treatment (C2D1) with the Guardant360 assay. Archived tissue (TP0) and study entry biopsies (TP1) were assayed for whole transcriptome, HER2 copy number, and mutations, with Ampli-Seq, and centrally for HER2 with CLIA assays. Patient responses were assessed with RECIST v1.1, and Molecular Response with the Guardant360 Response algorithm. RESULTS: The ORR in phase II was 7/22 (32%), which included all patients who had at least one dose of study therapy. In phase I, the ORR was 12/19 (63%), which included only patients who were considered evaluable, having received their first scan at 6 weeks. Central confirmation of HER2-positivity was found in 83% (30/36) of the TP0 samples. HER2-amplified ctDNA was found at C1D1 in 48% (20/42) of samples. Patients with ctHER2-amp versus non-amplified HER2 ctDNA determined in C1D1 ctDNA had a longer median progression-free survival (PFS): 480 days versus 60 days (P = 0.015). Molecular Response scores were significantly associated with both PFS (HR 0.28, 0.09-0.90, P = 0.033) and best response (P = 0.037). All five of the patients with ctHER2-amp at C1D1 who had undetectable ctDNA after study therapy had an objective response. Patients whose ctHER2-amp decreased on-treatment had better outcomes than patients whose ctHER2-amp remained unchanged. HER2 RNA levels show a correlation to HER2 CLIA IHC status and were significantly higher in patients with clinically documented responses compared to patients with progressive disease (P = 0.03). CONCLUSIONS: The following biomarkers were associated with better outcomes for patients treated with T-DM1 + neratinib: (1) ctHER2-amp (C1D1) or in TP1; (2) Molecular Response scores; (3) loss of detectable ctDNA; (4) RNA levels of HER2; and (5) on-treatment loss of detectable ctHER2-amp. HER2 transcriptional and IHC/FISH status identify HER2-low cases (IHC 1+ or IHC 2+ and FISH negative) in these heavily anti-HER2 treated patients. Due to the small number of patients and samples in this study, the associations we have shown are for hypothesis generation only and remain to be validated in future studies. Clinical Trials registration NCT02236000.
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Ado-Trastuzumab Emtansina , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Quinolinas , Receptor ErbB-2 , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Ado-Trastuzumab Emtansina/uso terapêutico , Pessoa de Meia-Idade , Quinolinas/uso terapêutico , Quinolinas/administração & dosagem , Idoso , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Biomarcadores Tumorais/genética , Mutação , Idoso de 80 Anos ou mais , Trastuzumab/uso terapêutico , Trastuzumab/administração & dosagem , Resultado do Tratamento , Metástase NeoplásicaRESUMO
PURPOSE: A single arm, phase II trial of carboplatin, nab-paclitaxel, and pembrolizumab (CNP) in metastatic triple-negative breast cancer (mTNBC) was designed to evaluate overall response rate (ORR), progression-free survival (PFS), duration of response (DOR), safety/tolerability, overall survival (OS), and identify pathologic and transcriptomic correlates of response to therapy. PATIENTS AND METHODS: Patients with ≤2 prior therapies for metastatic disease were treated with CNP regardless of tumor programmed cell death-ligand 1 status. Core tissue biopsies were obtained prior to treatment initiation. ORR was assessed using a binomial distribution. Survival was analyzed via the Kaplan-Meier method. Bulk RNA sequencing was employed for correlative studies. RESULTS: Thirty patients were enrolled. The ORR was 48.0%: 2 (7%) complete responses (CR), 11 (41%) partial responses (PR), and 8 (30%) stable disease (SD). The median DOR for patients with CR or PR was 6.4 months [95% confidence interval (CI), 4-8.5 months]. For patients with CR, DOR was >24 months. Overall median PFS and OS were 5.8 (95% CI, 4.7-8.5 months) and 13.4 months (8.9-17.3 months), respectively. We identified unique transcriptomic landscapes associated with each RECIST category of radiographic treatment response. In CR and durable PR, IGHG1 expression was enriched. IGHG1high tumors were associated with improved OS (P = 0.045) and were concurrently enriched with B cells and follicular helper T cells, indicating IGHG1 as a promising marker for lymphocytic infiltration and robust response to chemo-immunotherapy. CONCLUSIONS: Pretreatment tissue sampling in mTNBC treated with CNP reveals transcriptomic signatures that may predict radiographic responses to chemo-immunotherapy.
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Neoplasias de Mama Triplo Negativas , Humanos , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Perfilação da Expressão Gênica , Intervalo Livre de Progressão , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
The combination of Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) and endocrine therapy (ET) is the standard of care for hormone receptor-positive (HR + ), human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC). Currently, there are no robust biomarkers that can predict response to CDK4/6i, and it is not clear which patients benefit from this therapy. Since MBC patients with liver metastases have a poorer prognosis, developing predictive biomarkers that could identify patients likely to respond to CDK4/6i is clinically important. Here we show the ability of imaging texture biomarkers before and a few cycles after CDK4/6i therapy, to predict early response and overall survival (OS) on 73 MBC patients with known liver metastases who received palbociclib plus ET from two sites. The delta radiomic model was associated with OS in validation set (HR: 2.4; 95% CI, 1.06-5.6; P = 0.035; C-index = 0.77). Compared to RECIST response, delta radiomic features predicted response with area under the curve (AUC) = 0.72, 95% confidence interval (CI) 0.67-0.88. Our study revealed that radiomics features can predict a lack of response earlier than standard anatomic/RECIST 1.1 assessment and warrants further study and clinical validation.
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The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer address all aspects of management for breast cancer. The treatment landscape of metastatic breast cancer is evolving constantly. The therapeutic strategy takes into consideration tumor biology, biomarkers, and other clinical factors. Due to the growing number of treatment options, if one option fails, there is usually another line of therapy available, providing meaningful improvements in survival. This NCCN Guidelines Insights report focuses on recent updates specific to systemic therapy recommendations for patients with stage IV (M1) disease.
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Neoplasias da Mama , Humanos , Feminino , OncologiaRESUMO
INTRODUCTION: Treatment advances have improved outcomes in human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer (eBC) but certain patients remain at high risk of recurrence. Neoadjuvant therapy (NAT) has comparable outcomes to adjuvant therapy with the advantage of surgical down-staging, response assessment, informing prognosis, and tailoring adjuvant treatment. Thus, the standard of care for the majority of HER2-positive eBC has become a combination of chemotherapy and HER2-targeted agents given in the neoadjuvant setting. AREAS COVERED: Mounting evidence suggests that pathologic complete response after NAT translates to a favorable long-term prognosis. The efficacy and tolerability of post-NAT are key, particularly for patients with residual disease. This is demonstrated, for example, by the use of trastuzumab emtansine in the appropriate clinical setting and various new drugs under investigation. This review summarizes the current clinical management and exciting future directions to optimize outcomes in HER2-positive eBC. EXPERT OPINION: Targeted therapies such as trastuzumab deruxtecan, tucatinib, and immunotherapy have demonstrated impressive responses in metastatic breast cancer, including CNS disease. Incorporating these agents in the post-neoadjuvant space may improve the prognosis of HER2-positive eBC. Future research should prioritize the identification of biomarkers that personalize treatments to achieve maximum benefit and less toxicity.
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Neoplasias da Mama , Terapia Neoadjuvante , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológicoRESUMO
INTRODUCTION: Breast cancer cells can evade immune recognition by upregulating programmed death-ligand 1 (PD-L1) leading to decreased T cell function. Anti-PD-1 agents, like pembrolizumab, and anti-PD-L1 agents, such as atezolizumab and durvalumab, in combination with chemotherapy were found to have efficacy in metastatic triple-negative breast cancer (TNBC). With sub-optimal long-term outcomes in early-stage TNBC, this combination of immune checkpoint inhibition with chemotherapy was subsequently investigated. A robust immune microenvironment and extensive tumor antigen exposure in early-stage breast cancer is believed to facilitate response to checkpoint inhibitors. AREAS COVERED: This review focuses on studies that assess the role of neoadjuvant immune checkpoint inhibition along with chemotherapy. The results of key phase I, II and III trials using checkpoint inhibitors in early-stage breast cancer (ESBC) are reviewed along with foundational data from metastatic TNBC, including the role of biomarkers in predicting response to immunotherapy. EXPERT OPINION: Despite a clear role for neoadjuvant immune checkpoint inhibition in TNBC, many questions remain. The benefit of these agents in the neoadjuvant versus adjuvant setting is unclear and immune-related toxicity is a major concern. Additional studies are needed to elucidate which immune checkpoint inhibitor is most efficacious and best tolerated in early-stage TNBC.
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Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , Inibidores de Checkpoint Imunológico/farmacologia , Terapia Neoadjuvante/métodos , Imunoterapia , Microambiente TumoralRESUMO
The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. These NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of ductal carcinoma in situ and the workup and locoregional management of early stage invasive breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org.
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Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Carcinoma Intraductal não Infiltrante/terapia , Feminino , Humanos , OncologiaRESUMO
PURPOSE: The tumor-associated vasculature (TAV) differs from healthy blood vessels by its convolutedness, leakiness, and chaotic architecture, and these attributes facilitate the creation of a treatment-resistant tumor microenvironment. Measurable differences in these attributes might also help stratify patients by likely benefit of systemic therapy (e.g., chemotherapy). In this work, we present a new category of computational image-based biomarkers called quantitative tumor-associated vasculature (QuanTAV) features, and demonstrate their ability to predict response and survival across multiple cancer types, imaging modalities, and treatment regimens involving chemotherapy. EXPERIMENTAL DESIGN: We isolated tumor vasculature and extracted mathematical measurements of twistedness and organization from routine pretreatment radiology (CT or contrast-enhanced MRI) of a total of 558 patients, who received one of four first-line chemotherapy-based therapeutic intervention strategies for breast (n = 371) or non-small cell lung cancer (NSCLC, n = 187). RESULTS: Across four chemotherapy-based treatment strategies, classifiers of QuanTAV measurements significantly (P < 0.05) predicted response in held out testing cohorts alone (AUC = 0.63-0.71) and increased AUC by 0.06-0.12 when added to models of significant clinical variables alone. Similarly, we derived QuanTAV risk scores that were prognostic of recurrence-free survival in treatment cohorts who received surgery following chemotherapy for breast cancer [P = 0.0022; HR = 1.25; 95% confidence interval (CI), 1.08-1.44; concordance index (C-index) = 0.66] and chemoradiation for NSCLC (P = 0.039; HR = 1.28; 95% CI, 1.01-1.62; C-index = 0.66). From vessel-based risk scores, we further derived categorical QuanTAV high/low risk groups that were independently prognostic among all treatment groups, including patients with NSCLC who received chemotherapy only (P = 0.034; HR = 2.29; 95% CI, 1.07-4.94; C-index = 0.62). QuanTAV response and risk scores were independent of clinicopathologic risk factors and matched or exceeded models of clinical variables including posttreatment response. CONCLUSIONS: Across these domains, we observed an association of vascular morphology on CT and MRI-as captured by metrics of vessel curvature, torsion, and organizational heterogeneity-and treatment outcome. Our findings suggest the potential of shape and structure of the TAV in developing prognostic and predictive biomarkers for multiple cancers and different treatment strategies.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Biomarcadores , Carcinoma Pulmonar de Células não Pequenas/diagnóstico por imagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Quimiorradioterapia/métodos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Tomografia Computadorizada por Raios X , Microambiente TumoralRESUMO
Importance: Obesity increases the incidence and mortality from some types of cancer, but it remains uncertain whether intentional weight loss can decrease this risk. Objective: To investigate whether bariatric surgery is associated with lower cancer risk and mortality in patients with obesity. Design, Setting, and Participants: In the SPLENDID (Surgical Procedures and Long-term Effectiveness in Neoplastic Disease Incidence and Death) matched cohort study, adult patients with a body mass index of 35 or greater who underwent bariatric surgery at a US health system between 2004 and 2017 were included. Patients who underwent bariatric surgery were matched 1:5 to patients who did not undergo surgery for their obesity, resulting in a total of 30â¯318 patients. Follow-up ended in February 2021. Exposures: Bariatric surgery (n = 5053), including Roux-en-Y gastric bypass and sleeve gastrectomy, vs nonsurgical care (n = 25â¯265). Main Outcomes and Measures: Multivariable Cox regression analysis estimated time to incident obesity-associated cancer (a composite of 13 cancer types as the primary end point) and cancer-related mortality. Results: The study included 30â¯318 patients (median age, 46 years; median body mass index, 45; 77% female; and 73% White) with a median follow-up of 6.1 years (IQR, 3.8-8.9 years). The mean between-group difference in body weight at 10 years was 24.8 kg (95% CI, 24.6-25.1 kg) or a 19.2% (95% CI, 19.1%-19.4%) greater weight loss in the bariatric surgery group. During follow-up, 96 patients in the bariatric surgery group and 780 patients in the nonsurgical control group had an incident obesity-associated cancer (incidence rate of 3.0 events vs 4.6 events, respectively, per 1000 person-years). The cumulative incidence of the primary end point at 10 years was 2.9% (95% CI, 2.2%-3.6%) in the bariatric surgery group and 4.9% (95% CI, 4.5%-5.3%) in the nonsurgical control group (absolute risk difference, 2.0% [95% CI, 1.2%-2.7%]; adjusted hazard ratio, 0.68 [95% CI, 0.53-0.87], P = .002). Cancer-related mortality occurred in 21 patients in the bariatric surgery group and 205 patients in the nonsurgical control group (incidence rate of 0.6 events vs 1.2 events, respectively, per 1000 person-years). The cumulative incidence of cancer-related mortality at 10 years was 0.8% (95% CI, 0.4%-1.2%) in the bariatric surgery group and 1.4% (95% CI, 1.1%-1.6%) in the nonsurgical control group (absolute risk difference, 0.6% [95% CI, 0.1%-1.0%]; adjusted hazard ratio, 0.52 [95% CI, 0.31-0.88], P = .01). Conclusions and Relevance: Among adults with obesity, bariatric surgery compared with no surgery was associated with a significantly lower incidence of obesity-associated cancer and cancer-related mortality.
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Cirurgia Bariátrica , Neoplasias , Obesidade , Adulto , Cirurgia Bariátrica/métodos , Cirurgia Bariátrica/estatística & dados numéricos , Estudos de Coortes , Feminino , Gastrectomia/métodos , Gastrectomia/estatística & dados numéricos , Derivação Gástrica/métodos , Derivação Gástrica/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/epidemiologia , Neoplasias/etiologia , Neoplasias/mortalidade , Obesidade/complicações , Obesidade/epidemiologia , Obesidade/mortalidade , Obesidade/cirurgia , Obesidade Mórbida/complicações , Obesidade Mórbida/epidemiologia , Obesidade Mórbida/mortalidade , Obesidade Mórbida/cirurgia , Estudos Retrospectivos , Risco , Estados Unidos/epidemiologia , Redução de PesoRESUMO
PURPOSE: There are case reports of patients with both primary breast cancer (BC) and renal cell carcinoma (RCC). We explore the association between these two malignancies using SEER population data and our institutional records. METHODS: We studied the association between BC and RCC in the 2000-2016 Surveillance, Epidemiology, and End Results (SEER) database. We then reviewed our hospital records of patients with both BC and RCC and collected information including personal and family history of cancers, genetic testing, and patient outcomes. RESULTS: Of the 813,477 females diagnosed with BC in the SEER database, 1914 later developed RCC. The risk of developing RCC was significantly increased within the first 6 months, 7-12 months, and 1-5 years following BC diagnosis with standardized incidence ratios (SIRs) of 5.08 (95% CI 4.62-5.57), 2.09 (95% CI 1.8-2.42), and 1.15 (95% CI 1.06-1.24), respectively. Of 56,200 females with RCC, 1087 later developed BC. The risk of developing BC following RCC was elevated within the first 6 months (SIR of 1.45 [95% CI 1.20-1.73]). For our hospital patients, 437 had both BC and RCC. 427 (97.71%) were female, and 358 (81.92%) were white, and breast cancer was diagnosed before RCC in 246 (56.3%) patients. There were 15 germline mutations in those with genetic testing. CONCLUSION: Our findings suggest that BC patients are at higher risk of developing RCC and vice versa. BC tended to precede RCC, and patients frequently had personal histories of other malignancies and a family history of cancer, particularly, BC.
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Neoplasias da Mama , Carcinoma de Células Renais , Neoplasias Renais , Neoplasias da Mama/etiologia , Neoplasias da Mama/genética , Carcinoma de Células Renais/etiologia , Carcinoma de Células Renais/genética , Feminino , Humanos , Incidência , Neoplasias Renais/etiologia , Neoplasias Renais/genética , Fatores de Risco , Programa de SEERRESUMO
PURPOSE: Everolimus with exemestane (EVE+EXE) was FDA-approved to treat metastatic hormone receptor-positive breast cancer (mHRBC) based on BOLERO-2. However, none of those patients received prior CDK4/6 inhibitors. The purpose of this study is to evaluate the efficacy of EVE+EXE in mHRBC after CDK4/6 inhibitors. METHODS: A retrospective review of patients ≥18 years old with mHRBC treated with EVE+EXE, for ≥30 days, at our institution from January 1, 2012, to April 1, 2020 was conducted. Primary objective was to compare progression free survival (PFS) for EVE+EXE between patients with and without prior exposure to CDK4/6 inhibitors. Secondary outcomes included overall survival and safety. RESULTS: 192 patients were included in the study (n = 79, prior CDK4/6 inhibitor use; n = 113, no prior CDK4/6 inhibitor use). Baseline patient characteristics were similar between groups. Greater number of prior therapies before EVE+EXE use increased risk of disease progression (P = .017). Patients with prior CDK4/6 inhibitor use had a lower median PFS of 3.8 months (95% CI: 3.4-4.7) vs. 5.4 months (95% CI: 3.9-6.2) for patients without prior CDK4/6 inhibitor use, with a HR for progression of 1.46 (95% CI: 1.08 to 1.97, P = .013). Overall survival between groups was not significantly different. CONCLUSION: Patients who received a prior CDK4/6 inhibitor had a lower median PFS benefit from EVE+EXE compared to those who did not, without differences in overall survival. Although PFS is expected to decrease with subsequent lines of therapy, it is reasonable to use EVE+EXE after CDK4/6 inhibitors in selected patients, recognizing that additional benefit is modest.
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Androstadienos/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Everolimo/uso terapêutico , Receptor ErbB-2/metabolismo , Adolescente , Adulto , Idoso , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Qualidade de Vida , Receptor ErbB-2/efeitos dos fármacos , Estudos Retrospectivos , Resultado do TratamentoRESUMO
This article reviews the available literature that describes the incidence, diagnosis, mechanism, symptoms, and management of pulmonary toxicity induced by radiation therapy and current systemic medications used to treat breast cancer. An extensive literature search was conducted via Ovid Medline to identify all potentially relevant articles written in English from 2010 through January 2020. Additional relevant articles outside the time frame were included as needed. Although the risk of pulmonary toxicity from various breast cancer treatments is small in most instances, it can be fatal. Due to the high prevalence of breast cancer and the range of treatment options, healthcare providers should be aware of the risk of pulmonary toxicity from those treatments and how to prevent or manage complications.
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Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Fibrose Pulmonar/etiologia , Lesões por Radiação/etiologia , Pneumonite por Radiação/etiologia , Feminino , HumanosRESUMO
The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer-focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor-positive, HER2-negative breast cancer.
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Neoplasias da Mama , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/terapia , Terapia Combinada , Humanos , Masculino , OncologiaRESUMO
BACKGROUNDGenetics of estrogen synthesis and breast cancer risk has been elusive. The 1245AâC missense-encoding polymorphism in HSD3B1, which is common in White populations, is functionally adrenal permissive and increases synthesis of the aromatase substrate androstenedione. We hypothesized that homozygous inheritance of the adrenal-permissive HSD3B1(1245C) is associated with postmenopausal estrogen receptor-positive (ER-positive) breast cancer.METHODSA prospective study of postmenopausal ER-driven breast cancer was done for determination of HSD3B1 and circulating steroids. Validation was performed in 2 other cohorts. Adrenal-permissive genotype frequency was compared between postmenopausal ER-positive breast cancer, the general population, and postmenopausal ER-negative breast cancer.RESULTSProspective and validation studies had 157 and 538 patients, respectively, for the primary analysis of genotype frequency by ER status in White female breast cancer patients who were postmenopausal at diagnosis. The adrenal-permissive genotype frequency in postmenopausal White women with estrogen-driven breast cancer in the prospective cohort was 17.5% (21/120) compared with 5.4% (2/37) for ER-negative breast cancer (P = 0.108) and 9.6% (429/4451) in the general population (P = 0.0077). Adrenal-permissive genotype frequency for estrogen-driven postmenopausal breast cancer was validated using Cambridge and The Cancer Genome Atlas data sets: 14.4% (56/389) compared with 6.0% (9/149) for ER-negative breast cancer (P = 0.007) and the general population (P = 0.005). Circulating androstenedione concentration was higher with the adrenal-permissive genotype (P = 0.03).CONCLUSIONAdrenal-permissive genotype is associated with estrogen-driven postmenopausal breast cancer. These findings link genetic inheritance of endogenous estrogen exposure to estrogen-driven breast cancer.FUNDINGNational Cancer Institute, NIH (R01CA236780, R01CA172382, and P30-CA008748); and Prostate Cancer Foundation Challenge Award.
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Neoplasias da Mama/genética , Neoplasias da Mama/fisiopatologia , Estrogênios/uso terapêutico , Complexos Multienzimáticos/metabolismo , Progesterona Redutase/metabolismo , Esteroide Isomerases/metabolismo , Estrogênios/farmacologia , Feminino , Humanos , Pós-Menopausa , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Pseudocirrhosis is characterized by radiological changes in the liver that resemble cirrhosis, but with more rapid onset and progression. Though reported most frequently in patients with metastatic breast cancer, little is known about its prognostic factors and impact on breast cancer outcomes. METHODS: In this observational study, we reviewed abdominal CT and/or MRI scan reports of all patients with invasive breast cancer diagnosed at our center, during a ten-year period, to identify patients with pseudocirrhosis. Exclusion criteria included lack of baseline imaging, pre-existing cirrhosis, hepatitis B or C, other chronic liver diseases, or heavy alcohol use. Routine descriptive statistical measures were used. Survival distributions were estimated using Kaplan-Meier method, and Cox regression was used for multivariate analysis. Two-tailed p < 0.05 was considered significant. RESULTS: Eighty-six patients were included - all were females, median age was 57.5 years, and 90% were Caucasian; 86% of primary tumors were hormone-receptor positive and 17% were HER2 positive. Most patients (98%) had metastatic disease with liver involvement (94%), and were heavily pre-treated - 97% with chemotherapy, 85% with hormonal therapy, and 19% with anti-HER2 agents. Median interval from breast cancer diagnosis to pseudocirrhosis was 75.4 months (IQR 35.2-115.3 months). Thirty-six percentage of patients had ≥1 signs of portal hypertension and 49% had ≥1 signs of hepatocellular failure. Pseudocirrhosis led to permanent discontinuation of chemotherapy, endocrine therapy, and all systemic therapies in 29%, 31%, and 20% patients, respectively. Median overall survival from diagnosis of pseudocirrhosis was 10.0 months (95%CI 5.2-14.8 months). On multivariate analysis, coagulopathy, hyperbilirubinemia, hypoalbuminemia, and cancer progression were independently predictive of mortality. CONCLUSIONS: In this largest series, to date, of breast cancer with pseudocirrhosis, the latter was often complicated by portal hypertension and hepatocellular failure, and markedly impacted breast cancer management. Survival was shorter for patients who developed hepatocellular failure.
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BACKGROUND: The purpose of this study was to evaluate the impact of processes aimed at reducing time to treatment initiation (TTI) on minimizing the days spent to complete pretreatment visits and the associated costs for patients with nonmetastatic breast cancer. METHODS: System-wide initiatives were implemented in 2014 to minimize TTI, by incorporating multiple strategies (eg, creation of teams, patient liaisons, process mapping) and enhanced communication to increase coordinated visits. Average number of days spent to complete visits, TTI, and associated patient costs including driving expenses, parking, food, childcare, and lost wages were calculated and compared between the years 2015 and 2018. RESULTS: In 2015, the median TTI was 43.5 days and the average number of separate days spent to attend multidisciplinary visits prior to first treatment was 1.86. These were reduced to 29 days and 1.52 visits, respectively, in 2018 (p < 0.0001 for both). When evaluating treatment visits by surgical procedure, the average number of visits was reduced regardless of surgical procedure. The average number of visits was highest for patients undergoing mastectomy with reconstruction (2.34 in 2015, reduced to 1.65 in 2018, p < 0.0001). A single visit to complete treatment planning was associated with patient costs of $249 as compared with multiple trips costing $491 for 2 visits and up to $1,226 for 5 visits. CONCLUSIONS: In breast cancer patients, implementing processes to reduce time to treatment was associated with fewer visits required prior to treatment initiation, resulting in lower patient costs.