RESUMEN
BACKGROUND: Tumor immune infiltration and peripheral blood immune signatures have prognostic and predictive value in breast cancer. Whether distinct peripheral blood immune phenotypes are associated with response to neoadjuvant chemotherapy (NAC) remains understudied. METHODS: Peripheral blood mononuclear cells from 126 breast cancer patients enrolled in a prospective clinical trial (NCT02022202) were analyzed using Cytometry by time-of-flight with a panel of 29 immune cell surface protein markers. Kruskal-Wallis tests or Wilcoxon rank-sum tests were used to evaluate differences in immune cell subpopulations according to breast cancer subtype and response to NAC. RESULTS: There were 122 evaluable samples: 47 (38.5%) from patients with hormone receptor-positive, 39 (32%) triple-negative (TNBC), and 36 (29.5%) HER2-positive breast cancer. The relative abundances of pre-treatment peripheral blood T, B, myeloid, NK, and unclassified cells did not differ according to breast cancer subtype. In TNBC, higher pre-treatment myeloid cells were associated with lower pathologic complete response (pCR) rates. In hormone receptor-positive breast cancer, lower pre-treatment CD8 + naïve and CD4 + effector memory cells re-expressing CD45RA (TEMRA) T cells were associated with more extensive residual disease after NAC. In HER2 + breast cancer, the peripheral blood immune phenotype did not differ according to NAC response. CONCLUSIONS: Pre-treatment peripheral blood immune cell populations (myeloid in TNBC; CD8 + naïve T cells and CD4 + TEMRA cells in luminal breast cancer) were associated with response to NAC in early-stage TNBC and hormone receptor-positive breast cancers, but not in HER2 + breast cancer. TRIAL REGISTRATION: NCT02022202 . Registered 20 December 2013.
Asunto(s)
Neoplasias de la Mama , Inmunofenotipificación , Terapia Neoadyuvante , Humanos , Femenino , Terapia Neoadyuvante/métodos , Persona de Mediana Edad , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Adulto , Anciano , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leucocitos Mononucleares/metabolismo , Biomarcadores de Tumor/sangre , Pronóstico , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/sangre , Neoplasias de la Mama Triple Negativas/patología , Estudios Prospectivos , Resultado del Tratamiento , Quimioterapia Adyuvante/métodosRESUMEN
PURPOSE: Automated scalp cooling (ASC) is available to patients undergoing chemotherapy for breast cancer to decrease chemotherapy-induced alopecia. This study sought to elucidate patient and chemotherapy nursing perspectives on the ASC experience. METHODS: This is a survey-based study of chemotherapy nursing staff and patients with breast cancer regarding perceived efficacy, side effects, administration, support, and overall opinions of ASC. Chemotherapy nurses across a large, multi-regional tertiary healthcare system completed a one-time survey regarding their experiences in administering ASC. Breast cancer patients who utilized ASC were surveyed along with a control group who underwent alopecia-inducing chemotherapy without ASC use for comparison. RESULTS: The majority of nursing responses reported inadequate technical support, an increased burden of administering ASC compared to other clinical duties, and that they would not recommend ASC to a family member or friend. Patients who underwent ASC reported significantly less hair loss and were significantly less likely to shave their heads or wear a wig, but this did not translate into significant differences in body image or psychosocial wellbeing responses. Time investment was the most significant burden related to ASC. CONCLUSION: Patients using ASC reported significantly less hair loss compared to those not using ASC during alopecia-inducing breast cancer chemotherapy, but this did not translate to improved body image. The majority of chemotherapy nurses reported they lacked adequate support in administering ASC and would not recommend it. Enhanced nursing support may provide a means for improving the ASC experience for both nursing staff and patients.
Asunto(s)
Alopecia , Antineoplásicos , Neoplasias de la Mama , Hipotermia Inducida , Cuero Cabelludo , Humanos , Alopecia/inducido químicamente , Alopecia/prevención & control , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Persona de Mediana Edad , Antineoplásicos/efectos adversos , Adulto , Hipotermia Inducida/métodos , Anciano , Encuestas y Cuestionarios , Actitud del Personal de SaludRESUMEN
PURPOSE: We previously reported that postmenopausal women with estrogen receptor-α-positive breast cancer receiving adjuvant anastrozole 1 mg/day (ANA1) with estrone (E1) ≥1.3 pg/mL and estradiol (E2) ≥0.5 pg/mL [inadequate estrogen suppression (IES)] had a threefold increased risk of a breast cancer event. The objective of this study was to determine if increasing anastrozole to 10 mg/day (ANA10) could result in adequate estrogen suppression (AES: E1 <1.3 pg/mL and/or E2 <0.5 pg/mL) among those with IES on ANA1. PATIENTS AND METHODS: Postmenopausal women with estrogen receptor-α-positive breast cancer planning to receive adjuvant ANA1 were eligible. E1 and E2 were assessed pre- and post-8 to 10 weeks of ANA1. Those with IES were switched to 8- to 10-week cycles of ANA10 followed by letrozole 2.5 mg/day. E1 and E2 were assessed after each cycle. Anastrozole concentrations were measured post-ANA1 and post-ANA10. Primary analyses included patients who documented taking at least 80% of the planned treatment (adherent cohort). RESULTS: In total, 132 (84.6%) of 156 eligible patients were ANA1 adherent. IES occurred in 40 (30.3%) adherent patients. Twenty-five (78.1%) of 32 patients who began ANA10 were adherent, and AES was achieved in 19 (76.0%; 90% confidence interval, 58.1%-89.0%) patients. Anastrozole concentrations post-ANA1 and post-ANA10 did not differ by estrogen suppression status among adherent patients. AES was maintained/attained in 21 (91.3%) of 23 letrozole-adherent patients. CONCLUSIONS: Approximately 30% of ANA1-adherent patients had IES. Among those who switched to ANA10 and were adherent, 76% had AES. Further studies are required to validate emerging data that ANA1 results in IES for some patients and to determine the clinical benefit of switching to ANA10 or an alternative aromatase inhibitor.
Asunto(s)
Anastrozol , Neoplasias de la Mama , Nitrilos , Posmenopausia , Triazoles , Humanos , Anastrozol/administración & dosificación , Anastrozol/uso terapéutico , Anastrozol/efectos adversos , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Persona de Mediana Edad , Anciano , Triazoles/administración & dosificación , Triazoles/efectos adversos , Nitrilos/administración & dosificación , Nitrilos/efectos adversos , Estrógenos/administración & dosificación , Estadificación de Neoplasias , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/efectos adversos , Antineoplásicos Hormonales/uso terapéutico , Estudios Prospectivos , Estradiol/administración & dosificación , Estrona/sangre , Estrona/administración & dosificación , Inhibidores de la Aromatasa/administración & dosificación , Inhibidores de la Aromatasa/efectos adversosRESUMEN
Endocrine therapies (ET) with CDK4/6 inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of 22 ER+ breast cancer patient-derived xenografts (PDXs) demonstrated that PKMYT1, a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX organoids and xenografts, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.
RESUMEN
Importance: There has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes. Objective: To evaluate associations between clinical trial end points, namely pathologic complete response (pCR) and distant recurrence-free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race. Design, Setting, and Participants: This retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer. Analyses were conducted of associations between race and short- and long-term outcomes, overall and by receptor subtypes, and their association with 28 expression biomarkers. The trial enrolled 990 female patients between March 30, 2010, and November 5, 2016, with a primary tumor size of 2.5 cm or greater and clinical or molecular high risk based on MammaPrint or hormone receptor (HR)-negative/ERBB2 (formerly HER2 or HER2/neu)-positive subtyping across 9 arms. This data analysis was performed between June 10, 2021, and October 20, 2022. Exposure: Race, tumor receptor subtypes, and genomic biomarker expression of early breast cancer. Main Outcomes and Measures: The primary outcomes were pCR and DRFS assessed by race, overall, and by tumor subtype using logistic regression and Cox proportional hazards regression models. The interaction between 28 expression biomarkers and race, considering pCR and DRFS overall and within subtypes, was also evaluated. Results: The analytic sample included 974 participants (excluding 16 self-reporting as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or multiple races due to small sample sizes), including 68 Asian (7%), 120 Black (12%), and 786 White (81%) patients. Median (range) age at diagnosis was 47 (25-71) years for Asian, 49 (25-77) for Black, and 49 (23-73) years for White patients. The pCR rates were 32% (n = 22) for Asian, 30% for Black (n = 36), and 32% for White (n = 255) patients (P = .87). Black patients with HR-positive/ERBB2-negative tumors not achieving pCR had significantly worse DRFS than their White counterparts (hazard ratio, 2.28; 95% CI, 1.24-4.21; P = .01), with 5-year DRFS rates of 55% (n = 32) and 77% (n = 247), respectively. Black patients with HR-positive/ERBB2-negative tumors, compared with White patients, had higher expression of an interferon signature (mean [SD], 0.39 [0.87] and -0.10 [0.99]; P = .007) and, compared with Asian patients, had a higher mitotic score (mean [SD], 0.07 [1.08] and -0.69 [1.06]; P = .01) and lower estrogen receptor/progesterone receptor signature (mean [SD], 0.31 [0.90] and 1.08 [0.95]; P = .008). A transforming growth factor ß signature had a significant association with race relative to pCR and DRFS, with a higher signature associated with lower pCR and worse DRFS outcomes among Black patients only. Conclusions and Relevance: The findings show that women with early high-risk breast cancer who achieve pCR have similarly good outcomes regardless of race, but Black women with HR-positive/ERBB2-negative tumors without pCR may have worse DRFS than White women, highlighting the need to develop and test novel biomarker-informed therapies in diverse populations.
Asunto(s)
Neoplasias de la Mama , Grupos Raciales , Femenino , Humanos , Neoplasias de la Mama/genética , Estudios Retrospectivos , Transcriptoma , Respuesta Patológica Completa , Supervivencia sin EnfermedadRESUMEN
BACKGROUND: Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. Patients with TNBC are primarily treated with neoadjuvant chemotherapy (NAC). The response to NAC is prognostic, with reductions in overall survival and disease-free survival rates in those patients who do not achieve a pathological complete response (pCR). Based on this premise, we hypothesized that paired analysis of primary and residual TNBC tumors following NAC could identify unique biomarkers associated with post-NAC recurrence. METHODS AND RESULTS: We investigated 24 samples from 12 non-LAR TNBC patients with paired pre- and post-NAC data, including four patients with recurrence shortly after surgery (< 24 months) and eight who remained recurrence-free (> 48 months). These tumors were collected from a prospective NAC breast cancer study (BEAUTY) conducted at the Mayo Clinic. Differential expression analysis of pre-NAC biopsies showed minimal gene expression differences between early recurrent and nonrecurrent TNBC tumors; however, post-NAC samples demonstrated significant alterations in expression patterns in response to intervention. Topological-level differences associated with early recurrence were implicated in 251 gene sets, and an independent assessment of microarray gene expression data from the 9 paired non-LAR samples available in the NAC I-SPY1 trial confirmed 56 gene sets. Within these 56 gene sets, 113 genes were observed to be differentially expressed in the I-SPY1 and BEAUTY post-NAC studies. An independent (n = 392) breast cancer dataset with relapse-free survival (RFS) data was used to refine our gene list to a 17-gene signature. A threefold cross-validation analysis of the gene signature with the combined BEAUTY and I-SPY1 data yielded an average AUC of 0.88 for six machine-learning models. Due to the limited number of studies with pre- and post-NAC TNBC tumor data, further validation of the signature is needed. CONCLUSION: Analysis of multiomics data from post-NAC TNBC chemoresistant tumors showed down regulation of mismatch repair and tubulin pathways. Additionally, we identified a 17-gene signature in TNBC associated with post-NAC recurrence enriched with down-regulated immune genes.
Asunto(s)
Neoplasias de la Mama Triple Negativas , Humanos , Regulación hacia Abajo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Tubulina (Proteína) , Reparación de la Incompatibilidad de ADN , Multiómica , Estudios Prospectivos , Recurrencia Local de Neoplasia/genéticaRESUMEN
Patients with ER+/HER2+ breast cancer (BC) are less likely to achieve pathological complete response (pCR) after chemotherapy with dual HER2 blockade than ER-/HER2+ BC. Endocrine therapy plus trastuzumab is effective in advanced ER+/HER2+ BC. Inhibition of CDK4/6 and HER2 results in synergistic cell proliferation reduction. We combined palbociclib, letrozole, and trastuzumab (PLT) as a chemotherapy-sparing regimen. We evaluated neoadjuvant PLT in early ER+/HER2+ BC. Primary endpoint was pCR after 16 weeks. Research biopsies were performed for whole exome and RNA sequencing, PAM50 subtyping, and Ki67 assessment for complete cell cycle arrest (CCCA: Ki67 ≤ 2.7%). After 26 patients, accrual stopped due to futility. pCR (residual cancer burden-RCB 0) was 7.7%, RCB 0/I was 38.5%. Grade (G) 3/4 treatment-emergent adverse events occurred in 19. Among these, G3/4 neutropenia was 50%, hypertension 26.9%, and leucopenia 7.7%. Analysis indicated CCCA in 85% at C1 day 15 (C1D15), compared to 27% at surgery after palbociclib was discontinued. Baseline PAM50 subtyping identified 31.2% HER2-E, 43.8% Luminal B, and 25% Luminal A. 161 genes were differentially expressed comparing C1D15 to baseline. MKI67, TK1, CCNB1, AURKB, and PLK1 were among the genes downregulated, consistent with CCCA at C1D15. Molecular Signatures Database gene-sets analyses demonstrated downregulated processes involved in proliferation, ER and mTORC1 signaling, and DNA damage repair at C1D15, consistent with the study drug's mechanisms of action. Neoadjuvant PLT showed a pCR of 7.7% and an RCB 0/I rate of 38.5%. RNA sequencing and Ki67 data indicated potent anti-proliferative effects of study treatments. ClinicalTrials.gov- NCT02907918.
RESUMEN
Atezolizumab with chemotherapy has shown improved progression-free and overall survival in patients with metastatic PD-L1 positive triple negative breast cancer (TNBC). Atezolizumab with anthracycline- and taxane-based neoadjuvant chemotherapy has also shown increased pathological complete response (pCR) rates in early TNBC. This trial evaluated neoadjuvant carboplatin and paclitaxel with or without atezolizumab in patients with clinical stages II-III TNBC. The co-primary objectives were to evaluate if chemotherapy and atezolizumab increase pCR rate and tumor infiltrating lymphocyte (TIL) percentage compared to chemotherapy alone in the mITT population. Sixty-seven patients (ages 25-78 years; median, 52 years) were randomly assigned - 22 patients to Arm A, and 45 to Arm B. Median follow up was 6.6 months. In the modified intent to treat population (all patients evaluable for the primary endpoints who received at least one dose of combination therapy), the pCR rate was 18.8% (95% CI 4.0-45.6%) in Arm A, and 55.6% (95% CI 40.0-70.4%) in Arm B (estimated treatment difference: 36.8%, 95% CI 8.5-56.6%; p = 0.018). Grade 3 or higher treatment-related adverse events occurred in 62.5% of patients in Arm A, and 57.8% of patients in Arm B. One patient in Arm B died from recurrent disease during the follow-up period. TIL percentage increased slightly from baseline to cycle 1 in both Arm A (mean ± SD: 0.6% ± 21.0%) and Arm B (5.7% ± 15.8%) (p = 0.36). Patients with pCR had higher median TIL percentages (24.8%) than those with non-pCR (14.2%) (p = 0.02). Although subgroup analyses were limited by the small sample size, PD-L1-positive patients treated with chemotherapy and atezolizumab had a pCR rate of 75% (12/16). The addition of atezolizumab to neoadjuvant carboplatin and paclitaxel resulted in a statistically significant and clinically relevant increased pCR rate in patients with clinical stages II and III TNBC. (Funded by National Cancer Institute).
RESUMEN
PURPOSE: Quantify in vivo biomechanical tissue properties in various breast densities and in average risk and high-risk women using Magnetic Resonance Imaging (MRI)/MRE and examine the association between breast biomechanical properties and cancer risk based on patient demographics and clinical data. METHODS: Patients with average risk or high-risk of breast cancer underwent 3.0 T breast MR imaging and elastography. Breast parenchymal enhancement (BPE), density (from most recent mammogram), stiffness, elasticity, and viscosity were recorded. Within each breast density group (non-dense versus dense), stiffness, elasticity, and viscosity were compared across risk groups (average versus high). Separately for stiffness, elasticity, and viscosity, a multivariable logistic regression model was used to evaluate whether the MRE parameter predicted risk status after controlling for clinical factors. RESULTS: 50 average risk and 86 high-risk patients were included. Risk groups were similar in age, density, and menopausal status. Among patients with dense breasts, mean stiffness, elasticity, and viscosity were significantly higher in high-risk patients (N = 55) compared to average risk patients (N = 34; all p < 0.001). Stiffness remained a significant predictor of risk status (OR = 4.26, 95% CI [1.96, 9.25]) even after controlling for breast density, BPE, age, and menopausal status. Similar results were seen for elasticity and viscosity. CONCLUSION: A structurally based, quantitative biomarker of tissue stiffness obtained from MRE is associated with differences in breast cancer risk in dense breasts. Tissue stiffness could provide a novel prognostic marker to help identify high-risk women with dense breasts who would benefit from increased surveillance and/or risk reduction measures.
Asunto(s)
Neoplasias de la Mama , Diagnóstico por Imagen de Elasticidad , Mama/diagnóstico por imagen , Densidad de la Mama , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/epidemiología , Diagnóstico por Imagen de Elasticidad/métodos , Femenino , Humanos , Imagen por Resonancia MagnéticaRESUMEN
Systemic inflammation is believed to contribute to the distant recurrence of breast cancer. We evaluated serum samples obtained at diagnosis from 249 case:control pairs with stage II-III Her2-negative breast cancer with or without subsequent distant recurrence. Conditional logistic regression analysis, with models fit via maximum likelihood, were used to estimate hazard ratios (HRs) and test for associations of cytokines with distant recurrence risk. The only biomarker associated with a significantly increased distant recurrence risk when adjusted for multiple testing was the proinflammatory cytokine IL-6 (HR 1.37, 95% confidence intervals [CI] 1.15, 1.65, p = 0.0006). This prospective-retrospective study provides evidence indicating that higher levels of the cytokine IL-6 at diagnosis are associated with a significantly higher distant recurrence risk.
RESUMEN
IMPORTANCE: Breast cancer treatment can impact not only short-term health but may also affect longer-term quality of life (QOL). OBJECTIVE: To describe and evaluate factors associated with diminished QOL following completion of active treatment. DESIGN, SETTING, AND PARTICIPANTS: This was a secondary analysis of a randomized clinical trial included patients with lymph node-positive or high-risk lymph node-negative breast cancer who had undergone definitive surgery and were enrolled in ECOG-ACRIN E5103, a multisite phase 3 trial. A survey was administered 18 months after enrollment to patients enrolled between January and June 2010. Final analysis of the data took place from March to December 2021. INTERVENTIONS: Patients received adjuvant doxorubicin, cyclophosphamide, and paclitaxel with either bevacizumab or placebo. MAIN OUTCOMES AND MEASURES: QOL and health status assessed with the EuroQol 5-Dimension 3-Levels (EQ-5D-3L), EQ-visual analog scale (EQ-VAS), and the Functional Assessment of Cancer Therapy-Breast Cancer, with arm subscale (FACT-B+4). Groups were compared by Fisher exact test, Wilcoxon rank sum, or Kruskal-Wallis test. Multivariable linear regression was used to assess factors independently associated with FACT-B scores. RESULTS: Data at 18 months were available from 455 of 519 patients (87.7%) enrolled in the trial. Median (range) age at enrollment was 52 (25-76) years. No differences in QOL (median [range] FACT-B scores: group A, 123 [67-146]; group B, 114 [54-148]; group C, 117 [42-148]; P = .23) or health status (median [range] EQ-5D-3L index scores: group A, 0.83 [0.28-1.00]; group B, 0.83 [0.20-1.00]; group C, 0.83 [0.17-1.00], P = .80; median EQ-VAS: group A, 85 [20-100]; group B, 85 [0-100]; group C, 85 [0-100]; P = .79) were observed across treatment groups; results for subsequent analyses were therefore reported irrespective of primary treatment. Overall, half of patients (258 of 444 [58%]) reported at least some pain or discomfort; 170 (38%) reported symptoms of anxiety or depression. In multivariable analyses, mastectomy with radiation (vs breast conserving surgery) and Asian, Black, or American Indian or Alaska Native race (vs White race) were associated with lower QOL (mastectomy with radiation: coefficient: -5.5; 95% CI, -10.1 to -0.9; Asian, Black, or American Indian or Alaska Native race: coefficient: -7.3; 95% CI, -13.2, -1.4). CONCLUSIONS AND RELEVANCE: In this study, the addition of bevacizumab to chemotherapy was not negatively associated with QOL at 18 months. A substantial proportion of participants reported problems related to pain or discomfort and anxiety or depression, demonstrating persistent consequences for physical and psychosocial well-being in this heavily treated population. Many problems reported are amenable to intervention, underscoring the need for timely referral to supportive resources, especially for women of color and those who have more extensive local therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00433511.
Asunto(s)
Neoplasias de la Mama , Calidad de Vida , Bevacizumab/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/psicología , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Femenino , Humanos , Ganglios Linfáticos , Mastectomía , Dolor/tratamiento farmacológico , Calidad de Vida/psicologíaRESUMEN
BACKGROUND: Neoadjuvant therapy aims to preoperatively downstage breast cancer patients. We evaluated nodal upstaging in clinically node-negative (cN0) patients receiving neoadjuvant chemotherapy (NAC) and neoadjuvant endocrine therapy (NET). METHODS: cN0 patients undergoing neoadjuvant therapy from 2009 to 2018 were reviewed. Univariate and multivariate analyses evaluated rates of nodal upstaging. RESULTS: A total of 228 cN0 patients with a mean age of 55 years underwent neoadjuvant therapy for Stage I-III invasive carcinoma. Subtypes included ER+/HER2- = 93 (40%), HER2+ = 61 (27%), and triple negative (TNBC) = 74 (33%). Among ER+/HER2- patients, 65 (70%) underwent NET. Overall, 49 patients (21%) were upstaged due to occult nodal disease. Factors associated with higher rates of occult nodal disease included advanced stage on initial presentation (P = .008), larger presenting tumor size (P = .009), low/intermediate tumor grade (P = .025), and ER+/HER2- subtype (P < .001); incidence of occult nodal disease by subtype included: ER+/HER2- = 37%, HER2+ = 15%, TNBC = 8%. Patients experiencing a breast pCR had a significantly lower rate of nodal upstaging compared to those with residual tumor (4% vs. 96%, P < .001). On multivariate analysis, ER+/HER- patients exhibited higher risk of occult nodal disease when compared to patients with HER2+ (odds ratio [OR] = 3.4, 95% CI, 1.2-9.8, P = .003) and TNBC (OR = 5.7, 95% CI, 1.7-19.6, P = .003). Comparing NAC vs. NET in ER+/HER2- patients showed no difference in rates of occult nodal disease (39% vs. 35%, P = .13). CONCLUSIONS: ER+/HER2- subtype carries higher risk for occult nodal disease after neoadjuvant therapy; NAC versus NET in these patients does not affect nodal upstaging.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasia Residual/patología , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Adulto , Anciano , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Ganglios Linfáticos/patología , Metástasis Linfática , Persona de Mediana Edad , Terapia Neoadyuvante , Invasividad NeoplásicaRESUMEN
This prospective phase II clinical trial (Side Out 2) explored the clinical benefits of treatment selection informed by multi-omic molecular profiling (MoMP) in refractory metastatic breast cancers (MBCs). Core needle biopsies were collected from 32 patients with MBC at trial enrollment. Patients had received an average of 3.94 previous lines of treatment in the metastatic setting before enrollment in this study. Samples underwent MoMP, including exome sequencing, RNA sequencing (RNA-Seq), immunohistochemistry, and quantitative protein pathway activation mapping by Reverse Phase Protein Microarray (RPPA). Clinical benefit was assessed using the previously published growth modulation index (GMI) under the hypothesis that MoMP-selected therapy would warrant further investigation for GMI ≥ 1.3 in ≥ 35% of the patients. Of the 32 patients enrolled, 29 received treatment based on their MoMP and 25 met the follow-up criteria established by the trial protocol. Molecular information was delivered to the tumor board in a median time frame of 14 days (11-22 days), and targetable alterations for commercially available agents were found in 23/25 patients (92%). Of the 25 patients, 14 (56%) reached GMI ≥ 1.3. A high level of DNA topoisomerase I (TOPO1) led to the selection of irinotecan-based treatments in 48% (12/25) of the patients. A pooled analysis suggested clinical benefit in patients with high TOPO1 expression receiving irinotecan-based regimens (GMI ≥ 1.3 in 66.7% of cases). These results confirmed previous observations that MoMP increases the frequency of identifiable actionable alterations (92% of patients). The MoMP proposed allows the identification of biomarkers that are frequently expressed in MBCs and the evaluation of their role as predictors of response to commercially available agents. Lastly, this study confirmed the role of MoMP for informing treatment selection in refractory MBC patients: more than half of the enrolled patients reached a GMI ≥ 1.3 even after multiple lines of previous therapies for metastatic disease.
Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Inmunohistoquímica , Irinotecán , Estudios Prospectivos , Resultado del TratamientoRESUMEN
IMPORTANCE: Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. OBJECTIVE: To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. DESIGN, SETTING, AND PARTICIPANTS: The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) and ERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. INTERVENTIONS: Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. MAIN OUTCOMES AND MEASURES: Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). RESULTS: A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) and ERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01042379.
Asunto(s)
Neoplasias de la Mama , Terapia Neoadyuvante , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/patología , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Neoplasia Residual , Pronóstico , Supervivencia sin Progresión , Receptor ErbB-2/análisisRESUMEN
PURPOSE: Patient-derived xenografts (PDX) are a research tool for studying cancer biology and drug response phenotypes. While engraftment rates are higher for tumors with more aggressive characteristics, it is uncertain whether engraftment is prognostic for cancer recurrence. PATIENTS AND METHODS: In a prospective study of patients with breast cancer treated with neoadjuvant chemotherapy (NAC) with taxane ± trastuzumab followed by anthracycline-based chemotherapy, we report the association between breast cancer events and PDX engraftment using tumors derived from treatment naïve (pre-NAC biopsies from 113 patients) and treatment resistant (post-NAC at surgery from 34 patients). Gray test was used to assess whether the cumulative incidence of a breast cancer event differs with respect to either pre-NAC PDX engraftment or post-NAC PDX engraftment. RESULTS: With a median follow-up of 5.7 years, the cumulative incidence of breast cancer relapse did not differ significantly according to pre-NAC PDX engraftment (5-year rate: 13.6% vs. 13.4%; P = 0.89). However, the incidence of a breast event was greater for patients with post-NAC PDX engraftment (5-year rate: 50.0% vs. 19.6%), but this did not achieve significance (P = 0.11). CONCLUSIONS: In treatment-naïve breast cancer receiving standard NAC, PDX engraftment was not prognostic for breast cancer recurrence. Further study is needed to establish whether PDX engraftment in the treatment-resistant setting is prognostic for cancer recurrence.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Terapia Neoadyuvante , Trasplante Heterólogo , Ensayos Antitumor por Modelo de Xenoinjerto , Animales , Neoplasias de la Mama/cirugía , Femenino , Humanos , Ratones , Estudios Prospectivos , Resultado del TratamientoRESUMEN
PURPOSE: Metastatic breast cancer (mBC) remains incurable and is associated with low survival rates. This study assessed the efficacy and safety of liposomal irinotecan in heavily pretreated patients with mBC, with or without active brain metastases (BM). METHODS: Following the dose escalation phase and determination of recommended phase 2 dose, the expansion phase of this phase I, open-label, non-randomized study, assigned adult women to cohorts based on mBC subtype: cohort 1, hormone receptor +/human epidermal growth factor receptor 2-; cohort 2, triple-negative breast cancer; or cohort 3, any mBC subtype with active BM. Patients received liposomal irinotecan 50 or 70 mg/m2 free base every 2 weeks. Here, we report secondary outcomes including best overall response (BOR), objective response rate (ORR), and treatment-emergent adverse events (TEAEs). RESULTS: For non-central nervous system (non-CNS) disease across all cohorts (intent-to-treat population, N = 29), the ORR was 34.5% (95% confidence interval: 17.94-54.33), with a BOR of partial response in 10 patients (34.5%), stable disease in five (17.2%), progressive disease in 10 (34.5%); four patients were unevaluable (13.8%). The ORR for the CNS cohort was 30.0% (95% confidence interval: 6.67-65.25) using modified Response Evaluation Criteria in Solid Tumors. Common grade 3 or higher TEAEs were diarrhea (27.6%), nausea (17.2%), fatigue (13.8%), asthenia (10.3%), and hypokalemia (10.3%). Serious treatment-related TEAEs were reported in six patients (20.7%). No treatment-related TEAEs resulted in death. CONCLUSIONS: Liposomal irinotecan monotherapy demonstrated antitumor activity in heavily pretreated patients with mBC, with or without BM. The observed safety profile was consistent with that in previous studies. CLINICAL TRIAL REGISTRATION: Trial registration ID NCT01770353.
Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Humanos , Irinotecán , Tasa de Supervivencia , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Many American Indian (AI) and Alaska native (AN) patients do not complete guideline-concordant cancer care for the 4 most common cancers. Our aim was to better understand AI/AN attitudes toward radiation therapy (RT). Patients eligible for this survey study were AI/AN patients with cancer at the Phoenix Indian Medical Center who either received previous RT or were recommended to receive RT. An 18-item questionnaire was administered to each of the 50 participants from October 1, 2018, through February 15, 2019. Willingness to travel for RT was compared to respondent characteristics, concerns regarding RT, and obstacles to obtain RT. Duration of RT was important to 78% of patients: 24% would consider traveling 25 miles or more for a standard course, and 48% would travel that distance for a shorter course (P < .001). The top-ranked barriers to RT were transportation, cost of treatment, and insurance compatibility. The top-ranked concerns about RT were adverse effects, cost of treatment, and fear of RT. Concerns about adverse effects were associated with the radiation team's inability to explain the treatment (P = .05). Transportation concerns were significantly associated with accessibility (P = .02), communication with the RT team (P = .02), and fear of RT (P = .04). AI/AN patients are concerned about the adverse effects of RT and the logistics of treatment, particularly costs, transportation, and insurance compatibility. Use of culturally specific education and hypofractionation regimens may increase acceptance of RT for AI/AN patients with cancer, and this hypothesis will be tested in a future educational intervention-based study.
Asunto(s)
Indio Americano o Nativo de Alaska , Percepción , Radioterapia , Conocimientos, Actitudes y Práctica en Salud , Accesibilidad a los Servicios de Salud , Humanos , Aceptación de la Atención de Salud , Radioterapia/efectos adversos , Radioterapia/economíaRESUMEN
Importance: Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial. Objective: To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence-free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents. Design, Setting, and Participants: Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019. Interventions: Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide. Main Outcomes and Measures: Pathologic complete response and 3-year EFS and DRFS. Results: Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS. Conclusions and Relevance: The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study. Trial Registration: ClinicalTrials.gov Identifier: NCT01042379.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Terapia Neoadyuvante/efectos adversos , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Hidrocarburos Aromáticos con Puentes/efectos adversos , Ciclofosfamida/administración & dosificación , Ciclofosfamida/efectos adversos , Supervivencia sin Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Supervivencia sin Progresión , Modelos de Riesgos Proporcionales , Receptor ErbB-2/genética , Taxoides/administración & dosificación , Taxoides/efectos adversos , Trastuzumab/administración & dosificación , Trastuzumab/efectos adversos , Resultado del TratamientoRESUMEN
Worldwide, millions of women live with breast implants. Therefore, it is important that physicians be aware of an uncommon but possibly serious complication arising from breast implants: breast implant-associated anaplastic large cell lymphoma (BIA-ALCL). Breast implant-associated anaplastic large-cell lymphoma most commonly presents as a delayed fluid collection around a textured breast implant or as a mass in the capsule surrounding the implant. The exact pathogenesis of the disease remains unclear. The neoplastic cells of BIA-ALCL show strong uniform staining for CD30 and are consistently negative for activin receptor-like kinase 1. Patients with confirmed cases should be referred to a lymphoma specialist or breast medical oncologist for a complete oncologic evaluation before any surgical intervention. For disease confined to the fluid accumulation or capsule, or both, surgical removal of the implant and complete capsulectomy is the preferred treatment. Postoperative chemotherapy or radiation, or both, are not considered necessary for patients with limited-stage disease and are reserved for advanced disease stages. Generally, BIA-ALCL is a local disease that follows an indolent course and has an excellent prognosis. Although complete remission of disease has occurred in patients with BIA-ALCL, median overall survival is reduced. As of March 2018, approximately 529 unique, confirmed BIA-ALCL cases had been reported in 23 countries. To date, 16 patients have died from BIA-ALCL, and all had extracapsular involvement. The aim of this article is to summarize the diagnosis, evaluation, and management of BIA-ALCL, based on established guidelines, for all practitioners who may care for patients with breast implants.
Des millions de femmes vivent avec des implants mammaires dans le monde. Il est donc important que les médecins connaissent le lymphome anaplasique à grandes cellules associé aux implants mammaires (LAGC-IM), une complication peu fréquente, mais au potentiel grave. Le LAGC-IM prend généralement la forme d'une accumulation tardive de liquide autour d'un implant mammaire texturé ou d'une masse dans la capsule qui entoure l'implant. La pathogenèse exacte de la maladie demeure floue. Les cellules néoplasiques du LAGC-IM démontrent une coloration marquée et importante du CD30 et sont constamment négatives pour la kinase-1 analogue au récepteur d'activine. Les patients diagnostiqués doivent être dirigés vers un spécialiste des lymphomes ou un oncologue spécialisé en cancer du sein pour subir une évaluation oncologique complète avant toute intervention chirurgicale. Lorsque la maladie se limite à une accumulation de liquide, à la capsule ou à ces deux éléments, le traitement privilégié est l'exérèse chirurgicale de l'implant et la capsulectomie complète. La chimiothérapie postopératoire, la radiothérapie ou ces deux interventions ne sont pas considérées comme nécessaires pour les patientes ayant une maladie limitée, mais sont réservées aux maladies avancées. En général, le LAGC-IM est une maladie localisée à évolution lente et à l'excellent pronostic. Même si des patientes présentant un LAGC-IM se sont complètement rétablies, la survie médiane globale est réduite. En mars 2018, environ 529 cas uniques et confirmés de LAGC-IM avaient été signalés dans 23 pays. Jusqu'à présent, 16 patientes sont décédées d'un LAGC-IM, et toutes présentaient une atteinte extracapsulaire. Le présent article vise à résumer le diagnostic, l'évaluation et la prise en charge du LAGC-IM d'après des directives établies, et ce, pour tous les praticiens susceptibles de soigner des patientes ayant des implants mammaires.