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PURPOSE: Survivin/BIRC5 is a proliferation marker that is associated with poor prognosis in breast cancer and an attractive therapeutic target. However, BIRC5 has not been well studied among racially diverse populations where aggressive breast cancers are prevalent. EXPERIMENTAL DESIGN: We studied BIRC5 expression in association with clinical and demographic variables and as a predictor of recurrence in 2174 participants in the Carolina Breast Cancer Study (CBCS), a population-based study that oversampled Black (n = 1113) and younger (< 50 years; n = 1137) participants with breast cancer. For comparison, similar analyses were conducted in The Cancer Genome Atlas [TCGA N = 1094, Black (n = 183), younger (n = 295)]. BIRC5 was evaluated as a continuous and categorical variable (highest quartile vs. lower three quartiles). RESULTS: Univariate, continuous BIRC5 expression was higher in breast tumors from Black women relative to non-Black women in both estrogen receptor (ER)-positive and ER-negative tumors and in analyses stratified by stage (i.e., within Stage I, Stage II, and Stage III/IV tumors). Within CBCS and TCGA, BIRC5-high was associated with young age (< 50 years) and Black race, as well as hormone receptor-negative tumors, non-Luminal A PAM50 subtypes, advanced stage, and larger tumors (> 2 cm). Relative to BIRC5-low, BIRC5-high tumors were associated with poor 5-year recurrence-free survival (RFS) among ER-positive tumors, both in unadjusted models [HR (95% CI): 2.7 (1.6, 4.6)] and after adjustment for age and stage [Adjusted HR (95% CI): 1.87 (1.07, 3.25)]. However, this relationship was not observed among ER-negative tumors [Crude HR (95% CI): 0.7 (0.39, 1.2); Adjusted HR (95% CI): 0.67 (0.37, 1.2)]. CONCLUSION: Black and younger women with breast cancer have a higher burden of BIRC5-high tumors than older and non-Black women. Emerging anti-survivin treatment strategies may be an important future direction for equitable breast cancer outcomes.
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Neoplasias da Mama , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias da Mama/patologia , Survivina/genética , Negro ou Afro-AmericanoRESUMO
BACKGROUND: Breast cancer (BC) in women aged ≤40 years carrying germline pathogenetic variants (PVs) in BRCA1/2 genes is infrequent but often associated with aggressive features. Human epidermal growth factor receptor 2 (HER2)-low-expressing BC has recently emerged as a novel therapeutic target but has not been characterized in this rare patient subset. METHODS: Women aged ≤40 years with newly diagnosed early-stage HER2-negative BC (HER2-0 and HER2-low) and germline BRCA1/2 PVs from 78 health care centers worldwide were retrospectively included. Chi-square test and Student t-test were used to describe variable distribution between HER2-0 and HER2-low. Associations with HER2-low status were assessed with logistic regression. Kaplan-Meier method and Cox regression analysis were used to assess disease-free survival (DFS) and overall survival. Statistical significance was considered for p ≤ .05. RESULTS: Of 3547 included patients, 32.3% had HER2-low BC, representing 46.3% of hormone receptor-positive and 21.3% of triple-negative (TN) tumors. HER2-low vs. HER2-0 BC were more often of grade 1/2 (p < .001), hormone receptor-positive (p < .001), and node-positive (p = .003). BRCA2 PVs were more often associated with HER2-low than BRCA1 PVs (p < .001). HER2-low versus HER2-0 showed better DFS (hazard ratio [HR], 0.86; 95% CI, 0.76-0.97) in the overall population and more favorable DFS (HR, 0.78; 95% CI, 0.64-0.95) and overall survival (HR, 0.65; 95% CI, 0.46-0.93) in the TN subgroup. Luminal A-like tumors in HER2-low (p = .014) and TN and luminal A-like in HER2-0 (p = .019) showed the worst DFS. CONCLUSIONS: In young patients with HER2-negative BC and germline BRCA1/2 PVs, HER2-low disease was less frequent than expected and more frequently linked to BRCA2 PVs and associated with luminal-like disease. HER2-low status was associated with a modestly improved prognosis.
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Proteína BRCA1 , Proteína BRCA2 , Neoplasias da Mama , Mutação em Linhagem Germinativa , Receptor ErbB-2 , Humanos , Feminino , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudos Retrospectivos , Adulto , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Proteína BRCA1/genética , Proteína BRCA2/genética , Adulto Jovem , Intervalo Livre de Doença , PrognósticoRESUMO
For decades, chemotherapy has been the mainstay of breast cancer treatment. Novel therapies are expanding the therapeutic options and altering the treatment algorithms to manage this disease. The use and approval of immune checkpoint inhibitors (ICIs) and antibody-drug conjugates (ADCs) represent a few areas of progress. These therapies initially gained attention in the metastatic setting but have subsequently found a role in early-stage breast cancer. Although human epidermal growth factor receptor 2 (HER2) is at the center of ADC development, other surface antigens with a differential expression between tumor and normal cells may be appropriate for ADC targeting. This has led to the discovery of new ADCs targeting other receptors, including TROP-2, HER-3, and LIV-1, to name a few. Similarly, the addition of pembrolizumab in treating early-stage triple-negative breast cancer has led to exploring other ICIs in this setting. However, it has also raised important scientific questions regarding optimal patient selection, biomarkers that predict the success of ICIs, ideal chemotherapy partners, and the financial implications of bringing newer therapies to the forefront. In this review, we discuss the evolving landscape of ICIs and ADCs in managing early-stage breast cancer and provide an overview of potential future advancement in the field.
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Neoplasias da Mama , Imunoconjugados , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Inibidores de Checkpoint Imunológico , Algoritmos , Imunoconjugados/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Triple-negative breast cancer (TNBC) is a subtype of breast cancer with both inter- and intratumor heterogeneity, thought to result in a more aggressive course and worse outcomes. Neoadjuvant therapy (NAT) has become the preferred treatment modality of early-stage TNBC as it allows for the downstaging of tumors in the breast and axilla, monitoring early treatment response, and most importantly, provides important prognostic information that is essential to determining post-surgical therapies to improve outcomes. It focuses on combinations of systemic drugs to optimize pathologic complete response (pCR). Excellent response to NAT has allowed surgical de-escalation in ideal candidates. Further, treatment algorithms guide the systemic management of patients based on their pCR status following surgery. The expanding knowledge of molecular pathways, genomic sequencing, and the immunological profile of TNBC has led to the use of immune checkpoint inhibitors and targeted agents, including PARP inhibitors, further revolutionizing the therapeutic landscape of this clinical entity. However, subgroups most likely to benefit from these novel approaches in TNBC remain elusive and are being extensively studied. In this review, we describe current practices and promising therapeutic options on the horizon for TNBC, surgical advances, and future trends in molecular determinants of response to therapy in early-stage TNBC.
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PURPOSE OF REVIEW: In this article, we discuss recent advances in germline genetic testing for patients with breast cancer and highlight current limitations and impacts on clinical care. We also provide an update on the therapeutic implications of having a germline mutation, including targeted systemic therapy options for treating early and metastatic breast cancer. RECENT FINDINGS: Approximately 5 to 10% of women diagnosed with breast cancer have a pathogenic variant in a hereditary cancer susceptibility gene, which has significant implications for managing these patients. Previously, testing was done mainly to inform screening and risk-reduction treatment; however, more recently, germline genetic results have significant systemic therapy implications that can meaningfully improve outcomes in breast cancer patients, especially with oral poly-ADP-ribose polymerase (PARP) inhibitors. These systemic therapy advances implore a shift in paradigm for whom to test moving forward and how to modify the existing testing models to meet the increasing demand for germline testing, which is expected to grow exponentially.
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Proteína BRCA2 , Neoplasias da Mama , Humanos , Feminino , Proteína BRCA2/genética , Proteína BRCA1/genética , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Testes Genéticos , Células Germinativas/patologiaRESUMO
BACKGROUND: African American/Black women with breast cancer have poorer survival than White women, and this disparity persists even after adjusting for non-biological factors. Differences in tumor immune biology have been reported between Black and White women, and the tumor immune milieu could potentially drive racial differences in breast cancer etiology and outcome. METHODS: We examined the association of CD8+ cytotoxic T cells with clinical-pathological variables in the Women's Circle of Health Study (WCHS) population of predominantly Black breast cancer patients. We evaluated 688 invasive breast tumor samples (550 Black, 138 White) using immunohistochemical staining of tissue microarray slides. CD8+ T cells were scored for each patient tumor sample with digital image analysis. RESULTS: Black women had a significantly higher percentage of high-grade, estrogen receptor (ER)-negative, and triple-negative tumors than White women and significantly higher CD8+ T cell density (median 87.6/mm2 vs. 53.1/mm2; p < 0.001). Within the overall population and in the population of Black women only, CD8+ T cell density was significantly higher in younger patients and patients with high-grade and ER/PR-negative tumors. No significant associations were observed between CD8+ T cell density and overall survival or breast cancer-specific survival in the overall population, or when Black patients were analyzed as a separate group. However, when stratified by subtype, Black women with triple-negative breast cancer and high CD8+ T cell density showed a trend towards better overall survival in comparison with patients with low CD8+ T cell density (HR = 0.51; 95% CI 0.25-1.04). CONCLUSIONS: Our data raise the possibility that distinct mechanisms of immune cell action may occur in different racial groups.
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Negro ou Afro-Americano , Neoplasias da Mama/etnologia , Neoplasias da Mama/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos do Interstício Tumoral/imunologia , População Branca , Adulto , Idoso , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linfócitos T CD8-Positivos/patologia , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxa de Sobrevida , Saúde da Mulher , Adulto JovemRESUMO
Immune checkpoints are cell surface molecules that initiate regulatory pathways which have powerful control of CD8+ cytolytic T cell activity. Antagonistic and agonistic antibodies engaging these molecules have demonstrated profound impact on immune activation and have entered clinical use for the treatment of a variety of diseases. Over the past decade, antagonistic antibodies known as immune checkpoint inhibitors have become a new pillar of cancer treatment and have reshaped the therapeutic landscape in oncology. These agents differ in their mechanism of action and toxicity profiles compared to more traditional systemic cancer treatments such as chemo- and targeted therapies. This article reviews the pharmacology of this new class of agents.
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Imunoterapia , Neoplasias , Antígeno CTLA-4 , Humanos , Inibidores de Checkpoint Imunológico , Neoplasias/tratamento farmacológico , Neoplasias/imunologiaRESUMO
PURPOSE OF REVIEW: The outbreak of the novel coronavirus disease 2019 (COVID-19) has emerged to be the biggest global health threat worldwide, which has now infected over 1.7 million people and claimed more than 100,000 lives around the world. Under these unprecedented circumstances, there are no well-established guidelines for cancer patients. RECENT FINDINGS: The risk for serious disease and death in COVID-19 cases increases with advancing age and presence of comorbid health conditions. Since the emergence of the first case in Wuhan, China, in December 2019, tremendous research efforts have been underway to understand the mechanisms of infectivity and transmissibility of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a fatal virus responsible for abysmal survival outcomes. To minimize the mortality rate, it becomes prudent to identify symptoms promptly and employ treatments appropriately. Even though no cure has been established, multiple clinical trials are underway to determine the most optimal strategy. Managing cancer patients under these circumstances is rather challenging, given their vulnerable status and the aggressive nature of their underlying disease. In this comprehensive review, we discuss the impact of COVID-19 on health and the immune system of those affected, reviewing the latest treatment approaches and ongoing clinical trials. Additionally, we discuss challenges faced while treating cancer patients and propose potential approaches to manage this vulnerable population during this pandemic.
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Betacoronavirus , Infecções por Coronavirus/epidemiologia , Hospedeiro Imunocomprometido , Neoplasias/epidemiologia , Neoplasias/imunologia , Pneumonia Viral/epidemiologia , Antivirais/uso terapêutico , COVID-19 , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/transmissão , Mortalidade Hospitalar , Humanos , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/transmissão , Fatores de Risco , SARS-CoV-2RESUMO
BACKGROUND: Primary and secondary breast angiosarcoma is a rare and aggressive malignancy with limited published literature. Optimal management is mostly based on expert opinion. Our study aims to describe a single institution experience with breast angiosarcoma and evaluate other publications on this topic to further clarify prognostic outcomes and treatment modalities in this disease. METHODS: Twenty two cases of breast angiosarcoma from Roswell Park Comprehensive Cancer Center were retrospectively analyzed. Additionally, a systemic review and meta-analysis was conducted to study the association between survival outcomes, overall survival (OS), and recurrence-free survival (RFS) in both primary (PAS) and secondary breast angiosarcoma (SAS). RESULTS: 9 PAS patients (41%) and 13 SAS patients (59%) were retrospectively analyzed. No significant differences were noted in tumor characteristics and survival outcomes between PAS and SAS. Treatment modality had no significant effects on survival outcomes although adjuvant chemotherapy demonstrated a trend towards improved RFS in high grade tumors. 380 PAS and 595 SAS patients were included in the outcome meta-analysis. Survival outcomes were significantly worse with high grade tumors and tumor size of > 5 cm. Adjuvant radiation therapy demonstrated significantly better RFS, while adjuvant chemotherapy had no effect on survival outcomes. CONCLUSION: Tumor size and grade seem to be reliable predictors of survival in both PAS and SAS. Mastectomy does not seem to be adding any additional benefit to BCS. Adjuvant radiation therapy showed statistically significant RFS benefit, while adjuvant chemotherapy can be beneficial in high grade tumors.
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Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Hemangiossarcoma/patologia , Hemangiossarcoma/terapia , Idoso , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante , Feminino , Hemangiossarcoma/mortalidade , Humanos , Mastectomia , Pessoa de Meia-Idade , Prognóstico , Radioterapia Adjuvante , Estudos Retrospectivos , Análise de SobrevidaRESUMO
The COmorbidity TEst (COTE) is a Chronic Obstructive Pulmonary Disease (COPD)-specific co-morbidity score created to predict mortality. Before its wide application at the University of New Mexico we intended to validate it. The study was conducted at the University of New Mexico Hospital (UNMH) in Albuquerque, NM, USA, a tertiary academic hospital. Consecutive patients with the clinical diagnosis of COPD were identified using the hospital's medical records system and included if they were older than 40 years, had smoked at least 20 pack-years and their post bronchodilator forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) was <0.7 without an alternative diagnosis. The data collected included demographics, co-morbidities as described in the COTE, COPD-specific therapies, spirometry results and mortality. Of 317 patients 51.4% were male, average age was 65.6 ± 9.6 years and the mean post-bronchodilator FEV1 percent predicted (FEV1%) was 52.9 ± 16.9%. 31 (9.8%) patients were on triple long-acting bronchodilator inhaler therapy, 88 (27.8%) on two long-acting bronchodilators and 163 (51.4%) on at least one long-acting bronchodilator. The median follow-up was 3.5 years (IQR = 1.9-6.9). Fifty four patients died by the end of the follow-up period and their median COTE of 4 (IQR = 1-8) was significantly higher than for the survivors with COTE = 1 (IQR = 0-6; p = 0.002). In univariable analyses COTE was positively associated while FEV1%, body mass index (BMI) and gender were negatively associated with all-cause mortality. In multivariable analysis BMI, FEV1% and COTE remained independent predictors for mortality. The COTE is an independent predictor of mortality for COPD patients at UNMH.
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Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Área Sob a Curva , Índice de Massa Corporal , Broncodilatadores/farmacologia , Comorbidade , Quimioterapia Combinada , Feminino , Seguimentos , Volume Expiratório Forçado/efeitos dos fármacos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/mortalidade , Curva ROC , Estudos Retrospectivos , Fatores Sexuais , Espirometria , Capacidade VitalRESUMO
OBJECTIVE: The availability of targeted therapies for oncology patients is increasing. Available genomic tests to identify treatment-eligible patients include single gene tests and gene panel tests, including the whole-exome, whole-transcriptome OncoExTra test. We assessed the costs and clinical benefits of test choice. METHODS: A Microsoft Excel-based model was developed to evaluate test choice in patients with advanced/metastatic non-small cell lung cancer (NSCLC), breast, prostate, and colorectal cancer. Treatment pathways were based on NCCN guidelines and medical expert opinion. Inputs were derived from published literature. Annual economic results and lifetime clinical results with OncoExTra testing were projected per-tested-patient and compared with single gene testing and no testing. Separately, results were estimated for a US health plan without the OncoExTra test and with its use in 5% of patients. RESULTS: Compared with no genomic testing, OncoExTra test use increased costs by $4,915 per patient; however, 82%-92% of individuals across tumour types were identified as eligible for targeted therapy or a clinical trial. Compared with single gene testing, OncoExTra test use decreased costs by $9,966 per-patient-tested while increasing use of approved or investigational targeted therapies by 20%. When considering a hypothetical health plan with 1 million members, 858 patients were eligible for genomic testing. Using the OncoExTra test in 5% of those eligible, per-member per-month costs decreased by $0.003, ranging from cost-savings of $0.026 in NSCLC patients to a $0.009 increase in prostate cancer patients. Cost-savings were driven by reduced treatment costs with increased clinical trial enrolment and reduced direct and indirect medical costs associated with targeted treatments. LIMITATIONS: Limitations include the required simplifications in modelling complex conditions that may not fully reflect evolving real-world testing and treatment patterns. CONCLUSIONS: Compared to single-gene testing, results indicate that using next generation sequencing test such as OncoExTra identified more actionable alterations, leading to improved outcomes and reduced costs.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Neoplasias da Próstata , Humanos , Masculino , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Testes Genéticos , Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias da Próstata/genética , Feminino , Ensaios Clínicos como AssuntoRESUMO
Breast cancer poses one of the largest threats to women's health. Treatment continues to improve for all the subtypes of breast cancer, but some subtypes, such as triple negative breast cancer, still present a significant treatment challenge. Additionally, metastasis and local recurrence are two prevalent problems in breast cancer treatment. A newer type of therapy, immunotherapy, may offer alternatives to traditional treatments for difficult-to-treat subtypes. Immunotherapy engages the host's immune system to eradicate disease, with the potential to induce long-lasting, durable responses. However, systemic immunotherapy is only approved in a limited number of indications, and it benefits only a minority of patients. Furthermore, immune related toxicities following systemic administration of potent immunomodulators limit dosing and, consequently, efficacy. To address these safety considerations and improve treatment efficacy, interest in local delivery at the site of the tumor has increased. Numerous intratumorally delivered immunotherapeutics have been and are being explored clinically and preclinically, including monoclonal antibodies, cellular therapies, viruses, nucleic acids, cytokines, innate immune agonists, and bacteria. This review summarizes the current and past intratumoral immunotherapy clinical landscape in breast cancer as well as current progress that has been made in preclinical studies, with a focus on delivery parameters and considerations.
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Neoplasias da Mama , Imunoterapia , Humanos , Feminino , Neoplasias da Mama/terapia , Neoplasias da Mama/imunologia , Imunoterapia/métodos , AnimaisRESUMO
Background and Objectives: The 21-gene assay (the Oncotype DX Breast Recurrence Score® test) estimates the 10-year risk of distant recurrence in hormone receptor positive (HR+) and human epidermal growth factor receptor 2 negative (HER2-) early-stage breast cancer to inform adjuvant chemotherapy decisions. The cost-effectiveness of the 21-gene assay compared against standard clinical-pathological risk tools alone for HR+/HER2- early-stage breast cancer was assessed using an economic model informed by evidence from randomized controlled trials. Materials and Methods: A cost-effectiveness model consisted of a decision-tree to stratify patients according to their Recurrence Score (RS) results and the use of adjuvant chemotherapy, followed by a Markov component to estimate the long-term costs and outcomes of the chosen treatment. Distributions of patients and distant recurrence probabilities were derived from the TAILORx (N0) and RxPONDER (N1) trials. The model was evaluated from a healthcare payer and societal perspective. Endocrine therapy and chemotherapy use were informed using clinical expert opinion to reflect US clinical practice and were combined with Medicare drug costs (2021) to estimate the cost of treatment. Societal costs included lost productivity and patient out-of-pocket costs obtained from literature. Results: The Oncotype DX test generated more quality-adjusted life-years (QALYs) (N0: 0.25; N1: 0.08) at a lower cost (N0: -$13,395; N1: -$2526) compared to clinical-pathological risk alone from a societal cost perspective. The overall conclusions from the model did not change when considering a payer perspective. The main cost drivers were avoidance of distant recurrence for N0 (-$12,578), and the cost of adjuvant chemotherapy for N1 (-$2133). Lost productivity had a major impact in the societal perspective analysis (N0: -$4607; N1: -$1586). Conclusion: Adjuvant chemotherapy decisions based on the RS result led to more life year gains and lower healthcare costs (dominant) compared to using clinical-pathological risk factors alone among patients with HR+/HER2- N0 and N1 early-stage breast cancer.
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BACKGROUND: Alpelisib is an oral α-specific class I PI3K inhibitor approved in combination with fulvestrant for the treatment of PIK3CA-mutated hormone receptor-positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer. The tolerability of this drug with the oral chemotherapy capecitabine is unknown. PATIENTS AND METHODS: This phase I trial evaluated the dose-limiting toxicities (DLTs) and maximum tolerated dose (MTD) of alpelisib (250 mg or 300 mg daily for 3-weeks) with capecitabine (1000 mg/m2 twice daily for 2-weeks followed by a 1-week rest period) in patients with metastatic HER2-negative breast cancer, regardless of PIK3CA mutation status. RESULTS: Eighteen patients were treated with alpelisib-capecitabine. Half of the patients had HR+ breast cancer, and 16 had prior systemic therapy for metastatic disease. The MTD of alpelisib was 250 mg daily in combination with capecitabine 1000 mg/m2 twice daily. DLTs included hyperglycemia, QTc prolongation, fatigue, and chest pain. The most common grade 3 adverse event (AE) was hyperglycemia (28%). No grade 4 AEs were observed. Three patients discontinued therapy due to an AE. One-third of patients required dose reduction of both alpelisib and capecitabine. Four patients experienced a partial response and 8 patients experienced stable disease. The median progression-free survival was 9.7 months (95% CI 2.8-13.5 months) and median overall survival was 18.2 months (95% CI 7.2-35.2 months). Twelve patients had PIK3CA mutation testing completed, of these 2 had known or likely deleterious PIK3CA mutation. CONCLUSION: This study provides safety data for an oral combination therapy of alpelisib-capecitabine and defines tolerable doses for further study.
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BACKGROUND: OncotypeDx is a prognostic and predictive genomic assay used in early-stage hormone receptor-positive, HER2- (HR+/HER2-) breast cancer. It is used to inform adjuvant chemotherapy decisions, but not all eligible women receive testing. We aimed to assess variation in testing by demographics and geography, and to determine whether testing was associated with chemotherapy. METHODS: For 1,615 women in the Carolina Breast Cancer Study with HR+/HER2-, Stage I-II tumors, we estimated prevalence differences (PD) and 95% confidence intervals (CI) for receipt of OncotypeDx genomic testing in association with and sociodemographic characteristics. We assessed associations between testing and chemotherapy receipt overall and by race. Finally, we calculated the proportion of eligible women receiving OncotypeDx by county-level rurality, census tract-level socioeconomic status, and Area Health Education Center regions. RESULTS: 38% (N = 609) of potentially eligible women were tested, with lower testing prevalences in Black (31%; PD, -11%; 95% CI, -16%-6%) and low-income women (24%; PD, -20%; 95% CI, -29% to -11%) relative to non-Black and higher income women. Urban participants were less likely to be tested than rural participants, though this association varied by region. Among women with low genomic risk tumors, tested participants were 29% less likely to receive chemotherapy than untested participants (95% CI, -40% to -17%). Racial differences in chemotherapy were restricted to untested women. CONCLUSIONS: Both individual and area-level socioeconomics predict likelihood of OncotypeDx testing. IMPACT: Variable adoption of OncotypeDx by socioeconomics and across geographic settings may contribute to excess chemotherapy among patients with HR+/HER2- cancers. See related In the Spotlight, p. 635.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Pessoa de Meia-Idade , Adulto , Idoso , Classe Social , Disparidades em Assistência à Saúde/estatística & dados numéricos , Testes Genéticos/estatística & dados numéricos , Testes Genéticos/métodos , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genéticaRESUMO
PURPOSE: Cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6is) are an important component of treatment for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (MBC), but it is not known if patients might derive benefit from continuation of CDK4/6i with endocrine therapy beyond initial tumor progression or if the addition of checkpoint inhibitor therapy has value in this setting. METHODS: The randomized multicenter phase II PACE trial enrolled patients with hormone receptor-positive/HER2- MBC whose disease had progressed on previous CDK4/6i and aromatase inhibitor (AI) therapy. Patients were randomly assigned 1:2:1 to receive fulvestrant (F), fulvestrant plus palbociclib (F + P), or fulvestrant plus palbociclib and avelumab (F + P + A). The primary end point was investigator-assessed progression-free survival (PFS) in patients treated with F versus F + P. RESULTS: Overall, 220 patients were randomly assigned between September 2017 and February 2022. The median age was 57 years (range, 25-83 years). Most patients were postmenopausal (80.9%), and 40% were originally diagnosed with de novo MBC. Palbociclib was the most common previous CDK4/6i (90.9%). The median PFS was 4.8 months on F and 4.6 months on F + P (hazard ratio [HR], 1.11 [90% CI, 0.79 to 1.55]; P = .62). The median PFS on F + P + A was 8.1 months (HR v F, 0.75 [90% CI, 0.50 to 1.12]; P = .23). The difference in PFS with F + P and F + P + A versus F was greater among patients with baseline ESR1 and PIK3CA alterations. CONCLUSION: The addition of palbociclib to fulvestrant did not improve PFS versus fulvestrant alone among patients with hormone receptor-positive/HER2- MBC whose disease had progressed on a previous CDK4/6i plus AI. The increased PFS seen with the addition of avelumab warrants further investigation in this patient population.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Inibidores da Aromatase , Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Fulvestranto , Piperazinas , Piridinas , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Piridinas/uso terapêutico , Piperazinas/uso terapêutico , Inibidores da Aromatase/uso terapêutico , Pessoa de Meia-Idade , Fulvestranto/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Receptores de Estrogênio/metabolismo , Receptores de Estrogênio/análise , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Adulto , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Idoso de 80 Anos ou mais , Progressão da Doença , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Intervalo Livre de ProgressãoRESUMO
Human epidermal growth factor receptor 2-positive breast cancer (HER2+ BC) is an aggressive tumor type, accounting for 15% to 20% of the approximately 300,000 new BC cases in the United States each year. The goal of this review is to discuss the evolving landscape of therapies for HER2+ metastatic BC (mBC). Targeted therapies that have been the standard of care (SOC) for HER2+ mBC for almost a decade have greatly improved patient outcomes. The SOC for the first-line treatment of HER2+ mBC continues to be HER2-targeted monoclonal antibodies (mAbs)â¯+â¯a taxane, but recent updates in the second-line setting favor use of a newer HER2-targeted antibody-drug conjugate (ADC), trastuzumab deruxtecan, versus the prior SOC ADC, trastuzumab emtansine. Numerous options are now available in the third line and beyond, including tyrosine kinase inhibitor (TKI) regimens, newer mAbs, and other ADCs. The optimal course of treatment for individual patients can be guided by location of metastases, prior therapies, concomitant biomarkers, and monitoring and management of adverse events. Ongoing trials will further the evolution of the HER2+ mBC treatment landscape. Furthermore, next-generation ADCs, TKIs, and classes of drugs that have not been approved for the treatment of HER2+ mBC, including immune checkpoint inhibitors and cyclin-dependent kinase 4 and 6 inhibitors, are also being evaluated for their efficacy in the first and second line. Although the influx of new drugs may complicate treatment decisions for physicians, having a multitude of options will undoubtedly further improve patient outcomes and patient-centered care.
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Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Antineoplásicos/efeitos adversos , Receptor ErbB-2/metabolismo , Anticorpos Monoclonais Humanizados/uso terapêutico , Trastuzumab/uso terapêutico , Ado-Trastuzumab Emtansina/uso terapêuticoRESUMO
PURPOSE: Racial disparities in outcomes of breast cancer in the United States have widened over more than 3 decades, driven by complex biologic and social factors. In this review, we summarize the biological and social narratives that have shaped breast cancer disparities research across different scientific disciplines in the past, explore the underappreciated but crucial ways in which these 2 strands of the breast cancer story are interwoven, and present 5 key strategies for creating transformative interdisciplinary research to achieve equity in breast cancer treatment and outcomes. DESIGN: We first review the key differences in tumor biology in the United States between patients racialized as Black versus White, including the overrepresentation of triple-negative breast cancer and differences in tumor histologic and molecular features by race for hormone-sensitive disease. We then summarize key social factors at the interpersonal, institutional, and social structural levels that drive inequitable treatment. Next, we explore how biologic and social determinants are interwoven and interactive, including historical and contemporary structural factors that shape the overrepresentation of triple-negative breast cancer among Black Americans, racial differences in tumor microenvironment, and the complex interplay of biologic and social drivers of difference in outcomes of hormone receptor positive disease, including utilization and effectiveness of endocrine therapies and the role of obesity. Finally, we present 5 principles to increase the impact and productivity of breast cancer equity research. RESULTS: We find that social and biologic drivers of breast cancer disparities are often cyclical and are found at all levels of scientific investigation from cells to society. To break the cycle and effect change, we must acknowledge and measure the role of structural racism in breast cancer outcomes; frame biologic, psychosocial, and access factors as interwoven via mechanisms of cumulative stress, inflammation, and immune modulation; take responsibility for the impact of representativeness (or the lack thereof) in genomic and decision modeling on the ability to accurately predict the outcomes of Black patients; create research that incorporates the perspectives of people of color from inception to implementation; and rigorously evaluate innovations in equitable cancer care delivery and health policies. CONCLUSIONS: Innovative, cross-disciplinary research across the biologic and social sciences is crucial to understanding and eliminating disparities in breast cancer outcomes.
Assuntos
Equidade em Saúde , Racismo , Neoplasias de Mama Triplo Negativas , Humanos , Negro ou Afro-Americano , Atenção à Saúde , Microambiente Tumoral , Estados Unidos , Disparidades nos Níveis de Saúde , Disparidades em Assistência à SaúdeRESUMO
BACKGROUND AND OBJECTIVES: The Oncotype DX Breast Recurrence Score test is used to estimate distant recurrence risk of hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) early-stage breast cancer and inform decisions on the use of adjuvant chemotherapy. A model-based budget impact analysis compared the Oncotype DX test in combination with clinical-pathological risk against using clinical-pathological risk alone for HR+/HER2- node-negative (N0) and node-positive (N1; 1-3 axillary lymph nodes) early-stage breast cancer patients. MATERIALS AND METHODS: Test and medical costs associated with treatment of breast cancer were assessed through a US healthcare payer perspective. Distributions of patients by Recurrence Score result and distant recurrence probabilities with chemo-endocrine and endocrine therapy were derived from the TAILORx (N0) and RxPONDER (N1) trials. Changes in budget impact were evaluated over a 5-year horizon for a 1,000,000-member hypothetical health plan. RESULTS: With the Oncotype DX test, there was an incremental budget impact of $261,067 (per member per month (PMPM): $0.004), in the N0 population, and $56,143 (PMPM: $0.001) in the N1 population over the 5-year period. The largest budget impact reduction in the N0 population was attributed to reduced breast cancer recurrence costs (incremental: -$633,457, PMPM: -$0.011), while chemotherapy sparing reduced costs in the N1 population (incremental: -$94,884, PMPM: -$0.002). CONCLUSION: The clinical benefit of using the Oncotype DX test to inform adjuvant chemotherapy decisions has been shown in multiple randomized controlled trials. This analysis demonstrated that while using the Oncotype DX test to inform adjuvant chemotherapy decisions may slightly increase US healthcare costs over an initial 5-year time horizon (driven by a cost increase in the first year with cost savings reflected in remaining 4 years), there is significant scope for cost savings when assessing beyond this period due to avoided downstream costs of distant recurrence and long-term chemotherapy adverse events. PMPM costs also remain low across all populations examined, demonstrating a close-to-neutral budget impact.
Assuntos
Neoplasias da Mama , Recidiva Local de Neoplasia , Humanos , Feminino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Perfilação da Expressão Gênica , Quimioterapia Adjuvante , Custos de Cuidados de Saúde , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genéticaRESUMO
BACKGROUND: Cognitive difficulties have been described after chemotherapy for breast cancer, but there is no standard of care to improve cognitive outcomes in these patients. This trial examined the feasibility, tolerability, acceptability, and preliminary effects of memantine to prevent cognitive decline during chemotherapy for breast cancer. METHODS: Patients with stage I-III breast cancer, scheduled for neo/adjuvant chemotherapy, completed a cognitive battery prior to and 4 weeks after completing chemotherapy. Memantine (10 mg BID) was administered concurrent with chemotherapy. Our primary cognitive outcome was visual working memory assessed by the Delayed Matching to Sample test. We used the Brief Medication Questionnaire to assess acceptability. RESULTS: Of 126 patients approached, 56 (44%) enrolled. Forty-five (80%) received ≥1 dose of memantine and completed pre-post assessments. Seventy-six percent reported taking ≥90% of scheduled doses. Participants were mean age of 56, 77% White, and 57% had stage I disease. Sixty-four percent had stable or improved Delayed Matching to Sample test scores. Stable or improved cognition was observed in 87%-91% across objective cognitive domain composite measures. Sixty-six percent self-reported stable or improved cognitive symptoms. There were seven greater than or equal to grade 3 adverse events; two were possibly related to memantine. Only 5% reported that taking memantine was a disruption to their lives. CONCLUSIONS: Memantine was well-tolerated and consistently taken by a large majority of patients receiving breast cancer chemotherapy. The majority demonstrated stable or improved cognition from pre- to post-assessment. Randomized trials are needed to determine memantine's efficacy to ameliorate cognitive loss. TRIAL REGISTRATION: ClinicalTrials.gov NCT04033419.