RESUMO
Despite breast cancer being long thought to be "immunologically cold," within early, triple-negative breast cancer (TNBC), there has been exciting advances with the use of immune checkpoint modulation combined with neoadjuvant chemotherapy. We review the major trials that have investigated combination immunochemotherapy in the neoadjuvant setting, reviewing both the pathological complete response rates and the maturing data regarding event-free and overall survival. Strategies to deescalate adjuvant therapy in patients with preserving excellent clinical outcome, as well as exploration of combinatorial adjuvant therapies to improve outcome in those with extensive residual are the next-generation challenges. In addition to refinement of existing biomarkers, such as PD-L1, TILs, and tumor mutational burden (TMB), exploration of topics like the microbiome as both a biomarker and a therapeutic has shown promise in other cancer types, which motivates investigating these in breast cancer.
Assuntos
Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Terapia Neoadjuvante , Biomarcadores Tumorais , Imunoterapia , Terapia CombinadaRESUMO
BACKGROUND: The Affordable Care Act sought to improve access to health care for low-income individuals. This study aimed to assess whether expansion of Medicaid coverage increased rates of post-mastectomy reconstruction (PMR) for patients who had Medicaid or no insurance. METHODS: A retrospective analysis performed through the National Cancer Database examined women who underwent PMR and were uninsured or had Medicaid, private insurance, or Medicare, and whose race/ethnicity, age, and state expansion status were known. Trends in the use of PMR after passage of Medicaid expansion in 2014 were evaluated. RESULTS: In all states and at all time periods, patients with private insurance were about twice as likely to undergo PMR as patients who had Medicaid or no insurance. In 2016, only 28.7 % of patients with Medicaid or no insurance in nonexpansion states underwent PMR (p < 0.001) compared with 38.5 % of patients in expansion states (p < 0.001). Patients in expansion states also have higher levels of education, higher income, and greater likelihood of living in metropolitan areas. Additionally, patients in all states saw an increase in early-stage disease, with a concomitant reduction in late disease, but this change was greater in expansion states than in non-expansion states. CONCLUSIONS: Expansion states have larger proportions of patients undergoing PMR than non-expansion states. This difference stems from significant differences in income, education, comorbidities, race, and location. Large metropolitan areas have the largest number of patients undergoing PMR, whereas rural areas have the least.
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Neoplasias da Mama , Medicaid , Idoso , Neoplasias da Mama/cirurgia , Feminino , Humanos , Cobertura do Seguro , Seguro Saúde , Mastectomia , Medicare , Patient Protection and Affordable Care Act , Estudos Retrospectivos , Estados UnidosRESUMO
Advances in immunotherapy, most notably antibodies targeting the inhibitory immune receptors cytotoxic T-lymphocyte associated protein 4 (CTLA-4/CD152), programmed death protein 1 (PD-1/CD279) and programmed death-ligand 1 (PD-L1/B7H1/CD274) have become effective standard therapies in advanced malignancies including melanoma,1-4 merkel cell carcinoma5, urological cancers6-8, non-small cell lung cancer9-11, mis-match repair (MMR) deficient tumors12, and Hodgkin lymphoma with response rates ranging from 25 to 60% in the first and second line settings13,14. FDA approval has also been given for treatment for hepatocellular carcinoma, gastric cancer, triple negative breast cancer, cervical and head and neck cancers with response rates closer to 15 %15. Additionally, some clinical efficacy has been observed in ovarian cancer, mesothelioma, prostate cancer, diffuse large B cell lymphoma, follicular lymphoma, and both cutaneous and peripheral T-cell lymphoma. However, despite these successes, most patients will initially fail to respond to treatment and almost half of initial responders will develop secondary resistance to immunotherapy and progress. Moreover, many prevalent solid organ tumors remain resistant to immunotherapy including colorectal, pancreatic and hepatobiliary cancers. Therefore, new therapies are needed to increase both initial and durable response rates and to develop new mechanistic insights into pathways of immune resistance so that immunotherapy may become more widely available as a therapeutic option in common malignancies.
Assuntos
Antineoplásicos/uso terapêutico , Epigênese Genética/imunologia , Repressão Epigenética/imunologia , Neoplasias/terapia , Antineoplásicos/imunologia , Antígeno B7-H1/efeitos adversos , Antígeno B7-H1/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Antígeno CTLA-4/imunologia , Terapia Combinada , Humanos , Imunoterapia/efeitos adversos , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologiaRESUMO
BACKGROUND: Angiosarcoma of the breast is rare and aggressive. It can occur as a de novo tumor or secondary to breast cancer treatment. The purpose of this study is to analyze differences between patients with primary and secondary angiosarcoma of the breast and investigate potential risk factors for its development. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results program of the National Cancer Institute database was queried to identify patients with angiosarcoma of the breast, trunk, shoulder, and upper arm. The population-based incidence was analyzed. Primary and secondary angiosarcoma cases were identified and compared. Breast cancer characteristics of secondary angiosarcoma patients were compared with all breast cancer patients in the database who did not develop angiosarcoma. RESULTS: Overall, 904 patients were included, and 65.4% were secondary angiosarcomas. These patients had worse survival, were older, more likely to be White, more likely to have regionally advanced disease, and had angiosarcoma tumors of higher pathologic grade. Independent factors associated with development of secondary angiosarcoma among breast cancer patients included White race, older age, invasive tumor, lymph node removal, lumpectomy, radiation treatment, and left-sided tumor. Although the mean time to develop angiosarcoma after breast cancer diagnosis was 8.2 years, the risk continues to increase up to 30 years after breast cancer treatment. CONCLUSION: Angiosarcoma is rare but increasing in incidence. Secondary angiosarcomas are more common and exhibit more aggressive behavior. Several factors for angiosarcoma after breast cancer treatment could be identified, which may help us counsel and identify patients at risk.
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Neoplasias da Mama , Hemangiossarcoma , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/etiologia , Neoplasias da Mama/cirurgia , Feminino , Hemangiossarcoma/epidemiologia , Hemangiossarcoma/etiologia , Hemangiossarcoma/cirurgia , Humanos , Excisão de Linfonodo , Mastectomia SegmentarRESUMO
INTRODUCTION: Invasive apocrine carcinoma is a rare breast cancer that is frequently triple negative. Little is known about the characteristics of its molecular subtypes. We compared the incidence, demographics, and clinicopathologic features of this cancer with non-apocrine carcinomas stratified by molecular subtype. METHODS: Women with invasive apocrine cancer were retrospectively identified from the Surveillance, Epidemiology, and End Results (SEER) database. Clinicopathologic and demographic features were compared with non-apocrine carcinomas, both overall using data from 2004 to 2017 and stratified by molecular subtypes using data from 2010 to 2017. The life table method was used to determine the 7-year breast cancer-specific survival. RESULTS: Compared with non-apocrine cancers, apocrine cancers presented at a younger age, with larger, higher-grade tumors that were much more likely to be triple negative (50% vs. 11%) or human epidermal growth factor receptor 2 (HER2)-positive (28% vs. 15%) and less likely to be luminal (22% vs. 74%); however, the 7-year survival was the same at 85%. The characteristics varied dramatically by molecular type. Compared with non-apocrine triple-negative, apocrine triple-negative patients were less likely to be African American and were much older, with smaller, lower-grade tumors and much better survival (86% vs. 74%). In contrast, compared with luminal non-apocrine, apocrine luminal patients had larger, higher-grade tumors and worse survival (79% vs. 89%). CONCLUSIONS: Invasive apocrine carcinomas have more aggressive features than non-apocrine carcinomas but the breast cancer-specific survival is the same. Half of these apocrine tumors are triple negative but these have more favorable features and much better survival than non-apocrine triple-negative cancers.
Assuntos
Neoplasias Ósseas , Carcinoma Ductal de Mama , Neoplasias de Mama Triplo Negativas , Biomarcadores Tumorais , Feminino , Humanos , Estudos RetrospectivosRESUMO
OPINION STATEMENT: Treatment sequencing in early-stage breast cancer has significantly evolved in recent years, particularly in the triple negative (TNBC) and human epidermal growth factor receptor 2 (HER2)-positive subsets. Instead of surgery first followed by chemotherapy, several clinical trials showed benefits to administering systemic chemotherapy (and HER2-targeted therapies) prior to surgery. These benefits include more accurate prognostic estimates based on the extent of residual cancer that can also guide adjuvant treatment, and frequent tumor downstaging that can lead to smaller surgeries in patients with large tumors at diagnosis. Patients with extensive invasive residual cancer after neoadjuvant therapy are at high risk for disease recurrence, and two pivotal clinical trials, CREATE-X and KATHERINE, demonstrated improved recurrence free survival with adjuvant capecitabine and ado-trastuzumab-emtansine (T-DM1) in TNBC and HER2-positive residual cancers, respectively. Patients who achieve pathologic complete response (pCR) have excellent long-term disease-free survival regardless of what chemotherapy regimen induced this favorable response. This allows escalation or de-escalation of adjuvant therapy: patients who achieved pCR could be spared further chemotherapy, while those with residual cancer could receive additional chemotherapy postoperatively. Ongoing clinical trials are testing this strategy (CompassHER2-pCR: NCT04266249). pCR also provides an opportunity to assess de-escalation of locoregional therapies. Currently, for patients with residual disease in the lymph nodes (ypN+), radiation therapy entails coverage of the undissected axilla, and may include supra/infraclavicular/internal mammary nodes in addition to the whole breast or chest wall, depending on the type of surgery. Ongoing trials are testing the safety of omitting post-mastectomy breast and post-lumpectomy nodal irradiation (NCT01872975) as well as omitting axillary lymph node dissection (NCT01901094) in the setting of pCR. Additionally, evolving technologies such as minimal residual disease (MRD) monitoring in the blood during follow-up may allow early intervention with "second-line systemic adjuvant therapy" for patients with molecular relapse which might prevent impending clinical relapse.
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Neoplasia Residual/diagnóstico , Neoplasia Residual/terapia , Neoplasias/diagnóstico , Neoplasias/terapia , Biomarcadores Tumorais , Tomada de Decisão Clínica , Ensaios Clínicos como Assunto , Terapia Combinada , Gerenciamento Clínico , Humanos , Terapia Neoadjuvante , Neoplasias/etiologia , Neoplasias/mortalidade , Prognóstico , Retratamento , Resultado do TratamentoRESUMO
BACKGROUND: Communication between patients and health providers influences patient satisfaction, but it is unknown whether similarity in communication styles results in higher patient satisfaction. METHODS: This study was conducted in the Smilow Cancer Hospital Breast Center. During routine follow-up visits, patients completed a Communication Styles Assessment (CSA), health survey (SF-12), Princess Margaret Hospital Satisfaction with Doctor Questionnaire, and brief demographic form. Physicians and Advanced Practice Providers were also asked to complete the CSA. Patients and providers were blinded to each other's responses. A communication styles concordance score was calculated as the Pearson correlation between 80 binary CSA items for each provider/patient pair. Factors affecting patient satisfaction scores were assessed in mixed-effects models. RESULTS: In total, 330 patients were invited to participate; of these 289 enrolled and 245 returned surveys. One hundred seventy-four completed all survey components, and 18 providers completed the CSA. Among the factors considered, physical health score (effect size = 0.0058, 95% CI 0.00051 to 0.0011, p = 0.032) and employment status (0.12, 95% CI - 0.0094 to 0.25, p = 0.069) had the greatest impact on patient satisfaction. However, patients who were not employed and less physically healthy had significantly elevated satisfaction scores when their communication style was more similar to their provider's (1.52, 95% CI 0.66 to 2.38, p = 0.0016). CONCLUSIONS: Patients who were physically healthy and employed were generally more satisfied with their care. The similarity in communication styles of patients and providers had a greater impact on patient satisfaction for patients who were less physically healthy and not employed.
Assuntos
Emprego/psicologia , Satisfação do Paciente/estatística & dados numéricos , Adulto , Idoso , Comunicação , Feminino , Pessoal de Saúde , Nível de Saúde , Inquéritos Epidemiológicos , Humanos , Masculino , Pessoa de Meia-Idade , Relações Médico-PacienteRESUMO
BACKGROUND: Although surgical management of the axilla for breast cancer continues to evolve, axillary lymphadenectomy remains the standard of care for women with advanced nodal disease. We sought to evaluate national patterns of care in axillary surgery, and its association with overall survival (OS) among women with N2-3 invasive breast cancer. METHODS: Women (18-90 years) with clinical N2-3 invasive breast cancer who underwent axillary surgery were identified from the National Cancer Data Base (NCDB) from 2004 to 2013. Axillary surgery was categorized as sentinel lymph node biopsy (SLNB, 1-5 nodes) or axillary lymph node dissection (ALND, ≥ 10 nodes). Patient and treatment characteristics, trends over time, and overall survival (OS) were compared by surgical treatment. RESULTS: Overall, 22,156 patients were identified. At diagnosis, 68.5% had cN2 and 31.5% had cN3 disease. Treatment included: lumpectomy (27%), mastectomy (73%), adjuvant chemotherapy (53.4%), neoadjuvant chemotherapy (NAC) (39.7%), radiation (74%), and endocrine therapy (54.4%). In total, 9.9% (n = 2190) underwent SLNB and 90.1% (n = 19,966) underwent ALND. Receipt of SLNB was associated with private insurance, grade 3 disease, invasive ductal cancer, NAC, and lumpectomy (all p < 0.001). After adjustment for known covariates, including chemotherapy use, ALND was associated with improved survival [hazard ratio (HR) 0.68, p < 0.001] and this effect was similar for N2 and N3 patients (axillary surgery × cN-stage interaction p = 0.29). CONCLUSIONS: Axillary lymphadenectomy was associated with improved survival in patients presenting with clinical N2-3 invasive breast cancer. Further studies, particularly in the neoadjuvant setting, are needed to identify breast cancer patients with advanced nodal disease who may safely avoid a lesser extent of axillary surgery.
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Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/mortalidade , Carcinoma Lobular/mortalidade , Excisão de Linfonodo/mortalidade , Mastectomia/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Axila , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Carcinoma Lobular/cirurgia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Invasividade Neoplásica , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Biópsia de Linfonodo Sentinela , Taxa de Sobrevida , Adulto JovemAssuntos
Neoplasias da Mama , Mamoplastia , Mama/anormalidades , Neoplasias da Mama/cirurgia , Feminino , Humanos , Hipertrofia , MedicaidRESUMO
BACKGROUND: The use of routine CT imaging for surveillance in asymptomatic patients with cutaneous melanoma is controversial. We report our experience using a surveillance strategy that included CT imaging for a cohort of patients with high-risk melanoma. METHODS: A total of 466 patients with high-risk cutaneous melanoma enrolled in adjuvant immunotherapy trials were followed for tumor progression by physical examination, labs, and CT imaging as defined by protocol. Evaluations were obtained at least every 6 months for year 1, every 6 months for year 2, and then annually for the remainder of the 5-year study. Time to tumor progression, sites of recurrence, and the method of relapse detection were identified. RESULTS: The patient cohort consisted of 115 stage II patients, 328 stage III patients, and 23 patients with resected stage IV melanoma. The medium time to progression for the 225 patients who developed tumor progression was 7 months. Tumor progression was detected by patients, physician examination or routine labs, or by CT imaging alone in 27, 14, and 59% of cases respectively. Melanoma recurrences were noted to be locoregional in 36% of cases and systemic in 64% of cases. Thirty percent of patients with locoregional relapse and 75% of patients with systemic relapse were detected solely by CT imaging. CONCLUSIONS: CT imaging alone detected the majority of sites of disease progression in our patients with high-risk cutaneous melanoma. This disease was not heralded by symptoms, physical examination, or blood work. Although the benefit of the early detection of advanced melanoma is unknown, this experience is relevant because of the rapid development and availability of potentially curative immunotherapies.
Assuntos
Melanoma/diagnóstico , Melanoma/secundário , Recidiva Local de Neoplasia/diagnóstico , Vigilância da População/métodos , Autoexame , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/patologia , Tomografia Computadorizada por Raios X , Adolescente , Adulto , Idoso , Doenças Assintomáticas , Análise Química do Sangue , Ensaios Clínicos como Assunto , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Exame Físico , Adulto JovemRESUMO
BACKGROUND: The American College of Surgeons Oncology Group (ACOSOG) Z0011 trial established the safety of omitting axillary lymph node dissection (ALND) for early-stage breast cancer patients with limited nodal disease undergoing lumpectomy. We examined the extent of axillary surgery among women eligible for Z0011 based on patient age and tumor subtype. METHODS: Patients with cT1-2, cN0 breast cancers and one or two positive nodes diagnosed from 2009 to 2014 and treated with lumpectomy were identified in the National Cancer Data Base. Sentinel lymph node biopsy (SLNB) was defined as the removal of 1-5 nodes and ALND as the removal of 10 nodes or more. Tumor subtype was categorized as luminal, human epidermal growth factor 2-positive (HER2+), or triple-negative. Logistic regression was used to estimate the odds of receiving SLNB alone versus ALND. RESULTS: The inclusion criteria were met by 28,631 patients (21,029 SLNB-alone and 7602 ALND patients). Patients 70 years of age or older were more likely to undergo SLNB alone than ALND (27.0% vs 20.1%; p < 0.001). The radiation therapy use rate was 89.4% after SLNB alone and 89.7% after ALND. In the multivariate analysis, the uptake of Z0011 recommendations increased over time (2014 vs 2009: odds ratio [OR] 13.02; p < 0.001). Younger patients were less likely to undergo SLNB alone than older patients (age <40 vs ≥70: OR 0.59; p < 0.001). Patients with HER2+ (OR 0.89) or triple-negative disease (OR 0.79) (p < 0.001) were less likely to undergo SLNB alone than those with luminal subtypes. CONCLUSIONS: Among women potentially eligible for ACOSOG Z0011, the use of SLNB alone increased over time in all groups, but the extent of axillary surgery differed by patient age and tumor subtype.
Assuntos
Neoplasias da Mama/patologia , Ensaios Clínicos como Assunto , Seleção de Pacientes , Adulto , Fatores Etários , Idoso , Axila , Neoplasias da Mama/cirurgia , Bases de Dados Factuais , Feminino , Seguimentos , Humanos , Excisão de Linfonodo , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Biópsia de Linfonodo Sentinela , CirurgiõesRESUMO
Ductal carcinoma in situ (DCIS), once a rare entity, now comprises up to 30% of newly diagnosed breast cancers detected on mammography. It is now appreciated as a widely heterogeneous disease, with indolent lesions of minimal clinical significance on one end of the spectrum, and aggressive lesions with malignant invasive potential on the other. Therefore, the traditional guideline-concordant approach to treatment with surgery, radiation, and endocrine therapy may lead to overtreatment of certain patients, and insufficient treatment of others. Risk assessment using clinical and molecular prognostic tools is being investigated, addressing the possibility of delineating subpopulations that may be treated with more tailored therapy. This review will summarize the current trends in the diagnosis and management of DCIS and will highlight ongoing trials that are shaping future management of this entity.
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Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/terapia , Carcinoma Intraductal não Infiltrante/terapia , Mastectomia/tendências , Oncologia/tendências , Antineoplásicos Hormonais/efeitos adversos , Biópsia/tendências , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/mortalidade , Carcinoma Intraductal não Infiltrante/patologia , Quimioterapia Adjuvante/tendências , Difusão de Inovações , Feminino , Humanos , Imageamento por Ressonância Magnética/tendências , Mamografia/tendências , Mastectomia/efeitos adversos , Mastectomia/mortalidade , Seleção de Pacientes , Valor Preditivo dos Testes , Radioterapia (Especialidade)/tendências , Radioterapia Adjuvante/tendências , Fatores de Risco , Oncologia Cirúrgica/tendências , Resultado do TratamentoRESUMO
Adoptive transfer of ex vivo expanded tumor-infiltrating lymphocytes (TILs) have produced long-term response in metastatic cancers. TILs have traditionally been expanded from surgically resected specimens. Ultrasound-guided core needle biopsy (CNB) is an alternative method that avoids the morbidity of surgery and have added benefits which may include patients not amenable to surgery as well as the potential to produce TILs from multiple lesions in the same patient. We assessed the ability to produce and expand TILs from primary triple-negative breast cancer tumors from CNB (n=7) and demonstrate comparable expansion, phenotype and cytokine secretion after phorbol myristate acetate-ionomycin stimulation to TILs expanded from surgery (n=6). T cell Receptor clonality and diversity were also comparable between the two cohorts throughout the TIL culture. CNB is a safe and feasible method to obtain tumor tissue for TIL generation in patients with triple-negative breast cancer.
Assuntos
Imunoterapia Adotiva , Neoplasias de Mama Triplo Negativas , Humanos , Biópsia com Agulha de Grande Calibre , Neoplasias de Mama Triplo Negativas/terapia , Linfócitos do Interstício Tumoral/patologia , FenótipoRESUMO
PURPOSE: The incidence of triple-negative breast cancer (TNBC) is higher among Black or African American (AA) women, yet they are underrepresented in clinical trials. To evaluate safety and efficacy of durvalumab concurrent with neoadjuvant chemotherapy for stage I-III TNBC by race, we enrolled additional AA patients to a Phase I/II clinical trial. PATIENTS AND METHODS: Our study population included 67 patients. The primary efficacy endpoint was pathologic complete response (pCR; ypT0/is, N0) rate. χ2 tests were used to evaluate associations between race and baseline characteristics. Cox proportional hazards models were used to assess association between race and overall survival (OS) and event-free survival (EFS). Multivariate logistic regression analyses were used to evaluate associations between race and pCR, immune-related adverse events (irAE) and recurrence. RESULTS: Twenty-one patients (31%) self-identified as AA. No significant associations between race and baseline tumor stage (P = 0.40), PD-L1 status (0.92), and stromal tumor-infiltrating lymphocyte (sTIL) count (P = 0.57) were observed. pCR rates were similar between AA (43%) and non-AA patients (48%; P = 0.71). Three-year EFS rates were 78.3% and 71.4% in non-AA and AA patients, respectively [HR, 1.451; 95% confidence interval (CI), 0.524-4.017; P = 0.474]; 3-year OS was 87% and 81%, respectively (HR, 1.72; 95% CI, 0.481-6.136; P = 0.405). The incidence of irAEs was similar between AA and non-AA patients and no significant associations were found between irAEs and pathologic response. CONCLUSIONS: pCR rates, 3-year OS and EFS after neoadjuvant immunotherapy and chemotherapy were similar in AA and non-AA patients. Toxicities, including the frequency of irAEs, were also similar.
Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Terapia Neoadjuvante , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
PURPOSE: We examined gene expression, germline variant, and somatic mutation features associated with pathologic response to neoadjuvant durvalumab plus chemotherapy in basal-like triple-negative breast cancer (bTNBC). EXPERIMENTAL DESIGN: Germline and somatic whole-exome DNA and RNA sequencing, programmed death ligand 1 (PD-L1) IHC, and stromal tumor-infiltrating lymphocyte scoring were performed on 57 patients. We validated our results using 162 patients from the GeparNuevo randomized trial. RESULTS: Gene set enrichment analysis showed that pathways involved in immunity (adaptive, humoral, innate), JAK-STAT signaling, cancer drivers, cell cycle, apoptosis, and DNA repair were enriched in cases with pathologic complete response (pCR), whereas epithelial-mesenchymal transition, extracellular matrix, and TGFß pathways were enriched in cases with residual disease (RD). Immune-rich bTNBC with RD was enriched in CCL-3, -4, -5, -8, -23, CXCL-1, -3, -6, -10, and IL1, -23, -27, -34, and had higher expression of macrophage markers compared with immune-rich cancers with pCR that were enriched in IFNγ, IL2, -12, -21, chemokines CXCL-9, -13, CXCR5, and activated T- and B-cell markers (GZMB, CD79A). In the validation cohort, an immune-rich five-gene signature showed higher expression in pCR cases in the durvalumab arm (P = 0.040) but not in the placebo arm (P = 0.923) or in immune-poor cancers. Independent of immune markers, tumor mutation burden was higher, and PI3K, DNA damage repair, MAPK, and WNT/ß-catenin signaling pathways were enriched in germline and somatic mutations in cases with pCR. CONCLUSIONS: The TGFß pathway is associated with immune-poor phenotype and RD in bTNBC. Among immune-rich bTNBC RD, macrophage/neutrophil chemoattractants dominate the cytokine milieu, and IFNγ and activated B cells and T cells dominate immune-rich cancers with pCR.
Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Albuminas , Anticorpos Monoclonais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Ciclofosfamida , Doxorrubicina , Feminino , Humanos , Terapia Neoadjuvante , Paclitaxel , Fator de Crescimento Transformador beta , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Triple-negative breast cancer (TNBC) is considered one of the highest-risk subtypes of breast cancer and has dismal prognosis. Local recurrence rate after standard therapy in the early breast cancer setting can be upwards to 72% in 5 years, and in the metastatic setting, the 5-year overall survival is 12%. Due to the lack of receptor expression, there has been a paucity of targeted therapeutics available, with chemotherapy being the primary option for systemic treatment in both the neoadjuvant and metastatic setting. More recently, immunotherapy has revolutionized the landscape of cancer treatment, particularly immune checkpoint inhibitor (ICI) therapy, with FDA approval in over 20 types of cancer since 2011. Compared to other cancer types, breast cancer has been traditionally thought of as being immunologically cold; however, TNBC has demonstrated the most promise with immunotherapy use, a timely discovery due to its lack of targeted therapy options. In this review, we summarize the trials using checkpoint therapy in early and metastatic TNBC, as well as the development of biomarkers and the importance of immune related adverse events (IRAEs), in this disease process.
RESUMO
The goal of this Phase I/II trial is to assess the safety and efficacy of administering durvalumab concurrent with weekly nab-paclitaxel and dose-dense doxorubicin/cyclophosphamide (ddAC) neoadjuvant therapy for stages I-III triple-negative breast cancer. The primary endpoint is pathologic complete response (pCR:ypT0/is, ypN0). The response was correlated with PDL1 expression and stromal tumor-infiltrating lymphocytes (sTILs). Two dose levels of durvalumab (3 and 10 mg/kg) were assessed. PD-L1 was assessed using the SP263 antibody; ≥1% immune and tumor cell staining was considered positive; sTILs were calculated as the area occupied by mononuclear inflammatory cells over the total intratumoral stromal area. 59 patients were evaluable for toxicity and 55 for efficacy in the Phase II study (10 mg/kg dose). No dose-limiting toxicities were observed in Phase I. In Phase II, pCR rate was 44% (95% CI: 30-57%); 18 patients (31%) experienced grade 3/4 treatment-related adverse events (AE), most frequently neutropenia (n = 4) and anemia (n = 4). Immune-related grade 3/4 AEs included Guillain-Barre syndrome (n = 1), colitis (n = 2), and hyperglycemia (n = 2). Of the 50 evaluable patients for PD-L1, 31 (62%) were PD-L1 positive. pCR rates were 55% (95% CI: 0.38-0.71) and 32% (95% CI: 0.12-0.56) in the PD-L1 positive and negative groups (p = 0.15), respectively. sTIL counts were available on 52 patients and were significantly higher in the pCR group (p = 0.0167). Concomitant administration of durvalumab with sequential weekly nab-paclitaxel and ddAC neoadjuvant chemotherapy resulted in a pCR rate of 44%; pCR rates were higher in sTIL-high cancers.
RESUMO
Importance: The expansion of Medicaid sought to fill gaps in insurance coverage among low-income Americans. Although coverage has improved, little is known about the relationship between Medicaid expansion and breast cancer stage at diagnosis. Objective: To review the association of Medicaid expansion with breast cancer stage at diagnosis and the disparities associated with insurance status, age, and race/ethnicity. Design, Setting, and Participants: This cohort study used data from the National Cancer Database to characterize the relationship between breast cancer stage and race/ethnicity, age, and insurance status. Data from 2007 to 2016 were obtained, and breast cancer stage trends were assessed. Additionally, preexpansion years (2012-2013) were compared with postexpansion years (2015-2016) to assess Medicaid expansion in 2014. Data were analyzed from August 12, 2019, to January 19, 2020. The cohort included a total of 1â¯796â¯902 patients with primary breast cancer who had private insurance, Medicare, or Medicaid or were uninsured across 45 states. Main Outcomes and Measures: Percent change of uninsured patients with breast cancer and stage at diagnosis, stratified by insurance status, race/ethnicity, age, and state. Results: This study included a total of 1 796 902 women. Between 2012 and 2016, 71â¯235 (4.0%) were uninsured or had Medicaid. Among all races/ethnicities, in expansion states, there was a reduction in uninsured patients from 22.6% (4771 of 21 127) to 13.5% (2999 of 22 150) (P < .001), and in nonexpansion states, there was a reduction from 36.5% (5431 of 14â¯870) to 35.6% (4663 of 13 088) (P = .12). Across all races, there was a reduction in advanced-stage disease from 21.8% (4603 of 21 127) to 19.3% (4280 of 22 150) (P < .001) in expansion states compared with 24.2% (3604 of 14 870) to 23.5% (3072 of 13 088) (P = .14) in nonexpansion states. In African American patients, incidence of advanced disease decreased from 24.6% (1017 of 4136) to 21.6% (920 of 4259) (P < .001) in expansion states and remained at approximately 27% (27.4% [1220 of 4453] to 27.5% [1078 of 3924]; P = .94) in nonexpansion states. Further analysis suggested that the improvement was associated with a reduction in stage 3 diagnoses. Conclusions and Relevance: In this cohort study, expansion of Medicaid was associated with a reduced number of uninsured patients and a reduced incidence of advanced-stage breast cancer. African American patients and patients younger than 50 years experienced particular benefit. These data suggest that increasing access to health care resources may alter the distribution of breast cancer stage at diagnosis.