RESUMEN
Sacituzumab Govitecan (SG) is an antibody-drug conjugate that has demonstrated efficacy in patients with TROP-2 expressing epithelial cancers. In a xenograft model of intracranial breast cancer, SG inhibited tumor growth and increased mouse survival. We conducted a prospective window-of-opportunity trial (NCT03995706) at the University of Texas Health Science Center at San Antonio to examine the intra-tumoral concentrations and intracranial activity of SG in patients undergoing craniotomy for breast cancer with brain metastases (BCBM) or recurrent glioblastoma (rGBM). We enrolled 25 patients aged ≥18 years diagnosed with BCBM and rGBM to receive a single intravenous dose of SG at 10 mg/kg given one day before resection and continued on days 1 and 8 of 21-day cycles following recovery. The PFS was 8 months and 2 months for BCBM and rGBM cohorts, respectively. The OS was 35.2 months and 9.5 months, respectively. Grade≥3 AE included neutropenia (28%), hypokalemia (8%), seizure (8%), thromboembolic event (8%), urinary tract infection (8%) and muscle weakness of the lower limb (8%). In post-surgical tissue, the median total SN-38 was 249.8 ng/g for BCBM and 104.5 ng/g for rGBM, thus fulfilling the primary endpoint. Biomarker analysis suggests delivery of payload by direct release at target site and that hypoxic changes do not drive indirect release. Secondary endpoint of OS was 35.2 months for the BCBM cohort and 9.5 months for rGBM. Non-planned exploratory endpoint of ORR was 38% for BCBM and 29%, respectively. Exploratory endpoint of Trop-2 expression was observed in 100% of BCBM and 78% of rGBM tumors. In conclusion, SG was found to be well tolerated with adequate penetration into intracranial tumors and promising preliminary activity within the CNS. Trial Registration: Trial (NCT03995706) enrolled at Clinical Trials.gov as Neuro/Sacituzumab Govitecan/Breast Brain Metastasis/Glioblastoma/Ph 0: https://clinicaltrials.gov/study/NCT03995706?cond=NCT03995706 .
Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias Encefálicas , Neoplasias de la Mama , Glioblastoma , Inmunoconjugados , Recurrencia Local de Neoplasia , Humanos , Femenino , Glioblastoma/tratamiento farmacológico , Glioblastoma/patología , Neoplasias Encefálicas/secundario , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Persona de Mediana Edad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Adulto , Anciano , Inmunoconjugados/uso terapéutico , Camptotecina/análogos & derivados , Camptotecina/uso terapéutico , Estudios Prospectivos , Compuestos Bicíclicos Heterocíclicos con Puentes/uso terapéutico , Antígenos de Neoplasias/metabolismo , Moléculas de Adhesión Celular/metabolismoRESUMEN
BACKGROUND: The 21-gene recurrence score (RS) assay (Oncotype DX) is used to guide adjuvant chemotherapy use for patients with hormone receptor-positive, HER2 (human epidermal growth factor receptor 2)-negative, axillary node-negative breast cancer. Its role, however, in providing prognostic information for late distant recurrence when added to clinicopathologic prognostic factors is unknown. METHODS: A patient-specific meta-analysis including 10,004 women enrolled in three trials was updated using extended follow-up data from TAILORx, integrating the RS with histologic grade, tumor size, and age at surgery for the RSClin tool. Cox models integrating clinicopathologic factors and the RS were compared by using likelihood ratio (LR) tests. External validation of prognosis for distant recurrence in years 0 to 10 and 5 to 10 was performed in an independent cohort of 1098 women in a real-world registry. RESULTS: RSClin provided significantly more prognostic information than either the clinicopathologic factors (ΔLR chi-square, 86.2; P<0.001) or RS alone (ΔLR chi-square, 131.0; P<0.001). The model was prognostic in an independent cohort for distant recurrence by 10 years after diagnosis (standardized hazard ratio, 1.56; 95% confidence interval, 1.25 to 1.94), was associated with late distant recurrence risk between 5 and 10 years after diagnosis (standardized hazard ratio, 1.78; 95% confidence interval, 1.25 to 2.55), and approximated the observed 10-year distant recurrence risk (Lin concordance, 0.87) and 5- to 10-year distant recurrence risk (Lin concordance, 0.92). CONCLUSIONS: The 21-gene RS is prognostic for distant recurrence and overall survival in early breast cancer. A model integrating the 21-gene RS and clinicopathologic factors improved estimates of distant recurrence risk compared with either used individually and stratified late distant recurrence risk. (Funded by the National Cancer Institute, National Institutes of Health [U10CA180820, U10CA180794, UG1CA189859, U10CA180868, and U10CA180822] and others.).
Asunto(s)
Neoplasias de la Mama , Recurrencia Local de Neoplasia , Humanos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Femenino , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Pronóstico , Persona de Mediana Edad , Anciano , Adulto , Factores de RiesgoRESUMEN
PURPOSE: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer. METHODS: Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes. RESULTS: A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2-deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy. CONCLUSIONS: This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.
Asunto(s)
Neoplasias Ováricas , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Proteína BRCA1/genética , Platino (Metal) , Proteína BRCA2/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/epidemiología , Neoplasias de la Mama Triple Negativas/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/epidemiología , Neoplasias Ováricas/genética , Inestabilidad Genómica , Recombinación HomólogaRESUMEN
PURPOSE: Metastatic hormone receptor-positive (HR+) breast cancer initially responds to serial courses of endocrine therapy, but ultimately becomes refractory. Elacestrant, a new generation FDA-approved oral selective estrogen receptor degrader (SERD) and antagonist, has demonstrated efficacy in a subset of women with advanced HR+breast cancer, but there are few patient-derived models to characterize its effect in advanced cancers with diverse treatment histories and acquired mutations. METHODS: We analyzed clinical outcomes with elacestrant, compared with endocrine therapy, among women who had previously been treated with a fulvestrant-containing regimen from the recent phase 3 EMERALD Study. We further modeled sensitivity to elacestrant, compared with the currently approved SERD, fulvestrant in patient-derived xenograft (PDX) models and cultured circulating tumor cells (CTCs). RESULTS: Analysis of the subset of breast cancer patients enrolled in the EMERALD study who had previously received a fulvestrant-containing regimen indicates that they had better progression-free survival with elacestrant than with standard-of-care endocrine therapy, a finding that was independent estrogen receptor (ESR1) gene mutations. We modeled elacestrant responsiveness using patient-derived xenograft (PDX) models and in ex vivo cultured CTCs derived from patients with HR+breast cancer extensively treated with multiple endocrine therapies, including fulvestrant. Both CTCs and PDX models are refractory to fulvestrant but sensitive to elacestrant, independent of mutations in ESR1 and Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Alpha (PIK3CA) genes. CONCLUSION: Elacestrant retains efficacy in breast cancer cells that have acquired resistance to currently available ER targeting therapies. Elacestrant may be an option for patients with HR+/HER2- breast cancer whose disease progressed on fulvestrant in the metastatic setting. TRANSLATIONAL RELEVANCE: Serial endocrine therapy is the mainstay of management for metastatic HR+breast cancer, but acquisition of drug resistance highlights the need for better therapies. Elacestrant is a recently FDA-approved novel oral selective estrogen receptor degrader (SERD), with demonstrated efficacy in the EMERALD phase 3 clinical trial of refractory HR+breast cancer. Subgroup analysis of the EMERALD clinical trial identifies clinical benefit with elacestrant in patients who had received prior fulvestrant independent of the mutational status of the ESR1 gene, supporting its potential utility in treating refractory HR+breast cancer. Here, we use pre-clinical models, including ex vivo cultures of circulating tumor cells and patient-derived xenografts, to demonstrate the efficacy of elacestrant in breast cancer cells with acquired resistance to fulvestrant.
Asunto(s)
Neoplasias de la Mama , Células Neoplásicas Circulantes , Animales , Humanos , Femenino , Fulvestrant , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Receptores de Estrógenos , Antagonistas de Estrógenos/uso terapéutico , Modelos Animales de Enfermedad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoAsunto(s)
Neoplasias de la Mama , Ácidos Grasos Omega-3 , Femenino , Humanos , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/complicaciones , Ácidos Grasos Omega-3/uso terapéutico , Ácidos Grasos no Esterificados , Receptores de Estrógenos , Posmenopausia , Obesidad/complicaciones , Suplementos Dietéticos , Complicaciones Posoperatorias/prevención & controlRESUMEN
PURPOSE: Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. METHODS: This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations. RESULTS: Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). CONCLUSION: Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.
Asunto(s)
Neoplasias de la Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Quinasa 4 Dependiente de la Ciclina , Antagonistas de Estrógenos/uso terapéutico , Femenino , Humanos , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , TetrahidronaftalenosRESUMEN
PURPOSE: Racial and ethnic disparities have included a lack of access to both genetic testing and research, resulting in poor understanding of the genomic architecture in under-represented populations. The South Texas population is primarily of Hispanic background and has been largely devoid of genetic services. We extended access to this underserved population and uncovered genetic variants previously not observed, emphasizing the need to continually improve both genomic databases and clarification of variant significance to provide meaningful patient counseling. METHODS: This study consisted of a retrospective cohort review of patients seen through a cancer genetics education and service program across 24 counties in South Texas. In total, 1,595 individuals were identified as appropriate for cancer genetic counseling and 1,377 completed genetic testing. RESULTS: Eighty percent of those receiving genetic counseling self-identified as Hispanic, 16% as non-Hispanic White (NHW), 3% as African American, and 1% as other race/ethnicity. Of reported variants, 18.8% were pathogenic and 13.7% were reported as a variant of uncertain significance (VUS). VUS was reported in 17.2% of the Hispanic individuals compared with 9% NHW (P = .005). CONCLUSION: Individuals of Hispanic ethnicity were significantly more likely to harbor a VUS compared with NHW. The extended reach into our regional communities revealed a gap in the ability to accurately interpret genomic variation with implications for advising patients on screening, prevention, and management strategies. A higher percentage of VUS also emphasizes the challenge of continued follow-up amid existing barriers that led to disparities in access. As understanding of the variants develops, hopefully gaps in knowledge of the genomic landscape will be lessened with increased clarity to provide accurate cancer risk assessment and recommendations for implementing prevention initiatives.
Asunto(s)
Hispánicos o Latinos , Neoplasias , Pruebas Genéticas/métodos , Hispánicos o Latinos/genética , Humanos , Neoplasias/genética , Estudios Retrospectivos , Texas/epidemiologíaRESUMEN
BACKGROUND: The goal of this study was to characterize cannabis use among patients with breast cancer, including their reasons for and timing of use, their sources of cannabis information and products, their satisfaction with the information found, their perceptions of its safety, and their dialogue about cannabis with their physicians. METHODS: United States-based members of the Breastcancer.org and Healthline.com communities with a self-reported diagnosis of breast cancer within 5 years (age ≥ 18 years) were invited to participate in an anonymous online survey. After informed consent was obtained, nonidentifiable data were collected and analyzed. RESULTS: Of all participants (n = 612), 42% (n = 257) reported using cannabis for relief of symptoms, which included pain (78%), insomnia (70%), anxiety (57%), stress (51%), and nausea/vomiting (46%). Furthermore, 49% of cannabis users believed that medical cannabis could be used to treat cancer itself. Of those taking cannabis, 79% had used it during treatment, which included systemic therapies, radiation, and surgery. At the same time, few (39%) had discussed it with any of their physicians. CONCLUSIONS: A significant percentage of survey participants (42%) used cannabis to address symptoms; approximately half of these participants believed that cannabis could treat cancer itself. Most participants used cannabis during active cancer treatment despite the potential for an adverse event during this vulnerable time. Furthermore, most participants believed that cannabis was safe and were unaware that product quality varied widely and depended on the source. This study reviews the research on medicinal cannabis in the setting of these findings to help physicians to recognize its risks and benefits for patients with cancer. LAY SUMMARY: Almost half of patients with breast cancer use cannabis, most commonly during active treatment to manage common symptoms and side effects: pain, anxiety, insomnia, and nausea. However, most patients do not discuss cannabis use with their physicians. Instead, the internet and family/friends are the most common sources of cannabis information. Furthermore, most participants believe that cannabis products are safe and are unaware that the safety of many products is untested.
Asunto(s)
Neoplasias de la Mama , Cannabis , Marihuana Medicinal , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/epidemiología , Femenino , Humanos , Marihuana Medicinal/efectos adversos , Marihuana Medicinal/uso terapéutico , Náusea/inducido químicamente , Náusea/epidemiología , Encuestas y CuestionariosRESUMEN
Histone deacetylase inhibitors (HDACi) are identified as novel therapeutic agents, however, recent clinical studies suggested that they are marginally effective in treating triple negative breast cancer (TNBC). Here, we show that first-in-class Leukemia Inhibitory Factor Receptor (LIFRα) inhibitor EC359 could enhance the therapeutic efficacy of HDACi against TNBC. We observed that both targeted knockdown of LIFR with CRISPR or treatment with EC359 enhanced the potency of four different HDACi in reducing cell viability, cell survival, and enhanced apoptosis compared to monotherapy in TNBC cells. RNA-seq studies demonstrated oncogenic/survival signaling pathways activated by HDACi were attenuated by the EC359 + HDACi therapy. Importantly, combination therapy potently inhibited the growth of TNBC patient derived explants, cell derived xenografts and patient-derived xenografts in vivo. Collectively, our results suggest that targeted inhibition of LIFR can enhance the therapeutic efficacy of HDACi in TNBC.
Asunto(s)
Antineoplásicos/farmacología , Inhibidores de Histona Desacetilasas/farmacología , Subunidad alfa del Receptor del Factor Inhibidor de Leucemia/antagonistas & inhibidores , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Animales , Antineoplásicos/administración & dosificación , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Femenino , Inhibidores de Histona Desacetilasas/administración & dosificación , Ratones , Ratones SCIDRESUMEN
INTRODUCTION: Neoadjuvant endocrine therapy is often utilized to downstage Estrogen Receptor-positive (ER+) breast cancer prior to surgery. However, this approach is sometimes met with endocrine resistance mechanisms within the tumor. This trial examines the safety and efficacy of tamoxifen in combination with an mTORC1/2 inhibitor, TAK-228, in the neoadjuvant treatment of ER+ breast cancer. METHODS: In this single-arm, open-label trial, pre- and post-menopausal women were enrolled to receive neoadjuvant tamoxifen (20 mg daily) with TAK-228 (30 mg weekly) for 16 weeks prior to surgery. Patient had tissue sampling at baseline, week 6, and week 16. The primary endpoint was change in Ki-67 from baseline to 6 weeks. The toxicity, change in tumor size, pathologic complete response rate, PEPI score, and baseline Oncotype Dx score were also assessed. RESULTS: Twenty-eight women were enrolled on the trial, and 25 completed the entire study course. The combination of tamoxifen and TAK-228 resulted in a significant reduction in Ki-67 from 18.3 to 15.2% (p = 0.0023). The drug was also found to be safe and tolerable. While nausea and hyperglycemia were common side effects, these were manageable. The tumor size also significantly decreased with the treatment, with a median decrease of 0.75 cm (p < 0.0001). There were no pathologic complete responses. CONCLUSION: Tamoxifen and TAK-228 was safe and well tolerated neoadjuvant treatment for ER+ breast cancer, preliminary evidence of activity with significant reduction in both Ki-67 and tumor size, warranting further evaluation in a larger study.
Asunto(s)
Neoplasias de la Mama , Terapia Neoadyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzoxazoles , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Hormonas/uso terapéutico , Humanos , Nitrilos/uso terapéutico , Pirimidinas , Receptor ErbB-2/genética , Receptores de Estrógenos , Tamoxifeno/uso terapéutico , Resultado del Tratamiento , Triazoles/uso terapéuticoRESUMEN
PURPOSE: As monotherapies, eribulin (chemotherapy) and pembrolizumab (immunotherapy) have shown promise for patients with metastatic triple-negative breast cancer (mTNBC). This phase Ib/II study examined eribulin plus pembrolizumab as a potential mTNBC treatment in first-line and later-line settings. PATIENTS AND METHODS: In this open-label, single-arm, phase Ib/II study, eligible patients had mTNBC, measurable disease, and ≤2 prior systemic anticancer therapies in the metastatic setting. Patients were enrolled by number of prior systemic anticancer therapies (stratum 1: 0 vs stratum 2: 1-2) in the metastatic setting and further analyzed by tumor programmed death-ligand 1 (PD-L1) expression status. All patients received intravenous eribulin 1.4 mg/m2 on day 1 and day 8, plus intravenous pembrolizumab 200 mg on day 1, of 21-day cycles. The primary objectives were the safety, tolerability, and objective response rate (ORR) of this combination. RESULTS: The study included 167 patients (phase Ib, n = 7; phase II, n = 160). The most common treatment-emergent adverse events were fatigue (66%), nausea (58%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). ORRs were 25.8% [95% confidence interval (CI): 15.8-38.0] for stratum 1 (n = 66) and 21.8% (95% CI: 14.2-31.1) for stratum 2 (n = 101). Patients with PD-L1-positive tumors (combined positive score ≥1) had numerically higher ORR than those with PD-L1-negative tumors, particularly in stratum 1 [stratum 1: 34.5% (95% CI: 17.9-54.3) vs 16.1% (95% CI: 5.5-33.7); stratum 2, 24.4% (95% CI: 12.9-39.5) vs 18.2% (95% CI: 8.2-32.7)]. CONCLUSIONS: Eribulin plus pembrolizumab was generally well tolerated and showed promising antitumor activity in mTNBC. Efficacy outcomes appeared influenced by line of therapy and PD-L1 status.
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Furanos/administración & dosificación , Cetonas/administración & dosificación , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Femenino , Expresión Génica , Humanos , Infusiones Intravenosas , Persona de Mediana Edad , Seguridad , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/diagnóstico , Neoplasias de la Mama Triple Negativas/genéticaRESUMEN
BACKGROUND: Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment. METHODS: The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided. RESULTS: Of 9719 eligible women with hormone receptor-positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25. CONCLUSIONS: Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.
Asunto(s)
Pueblo Asiatico/estadística & datos numéricos , Población Negra/estadística & datos numéricos , Neoplasias de la Mama/etnología , Hispánicos o Latinos/estadística & datos numéricos , Población Blanca/estadística & datos numéricos , Adulto , Anciano , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Comorbilidad , Intervalos de Confianza , Receptor alfa de Estrógeno/genética , Receptor alfa de Estrógeno/metabolismo , Femenino , Humanos , Cobertura del Seguro/estadística & datos numéricos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Menopausia , Persona de Mediana Edad , Recurrencia Local de Neoplasia/etnología , Recurrencia Local de Neoplasia/genética , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Receptor ErbB-2/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Chromothripsis is an event of genomic instability leading to complex chromosomal alterations in cancer. Frequent long-range chromatin interactions between transcription factors (TFs) and targets may promote extensive translocations and copy-number alterations in proximal contact regions through inappropriate DNA stitching. Although studies have proposed models to explain the initiation of chromothripsis, few discussed how TFs influence this process for tumor progression. METHODS: This study focused on genomic alterations in amplification associated regions within chromosome 17. Inter-/intra-chromosomal rearrangements were analyzed using whole genome sequencing data of breast tumors in the Cancer Genome Atlas (TCGA) cohort. Common ERα binding sites were defined based on MCF-7, T47D, and MDA-MB-134 breast cancer cell lines using univariate K-means clustering methods. Nanopore sequencing technology was applied to validate frequent rearrangements detected between ATC loci on 17q23 and an ERα hub on 20q13. The efficacy of pharmacological inhibition of a potentially druggable target gene on 17q23 was evaluated using breast cancer cell lines and patient-derived circulating breast tumor cells. RESULTS: There are five adjoining regions from 17q11.1 to 17q24.1 being hotspots of chromothripsis. Inter-/intra-chromosomal rearrangements of these regions occurred more frequently in ERα-positive tumors than in ERα-negative tumors. In addition, the locations of the rearrangements were often mapped within or close to dense ERα binding sites localized on these five 17q regions or other chromosomes. This chromothriptic event was linked to concordant upregulation of 96 loci that predominantly regulate cell-cycle machineries in advanced luminal tumors. Genome-editing analysis confirmed that an ERα hub localized on 20q13 coordinately regulates a subset of these loci localized on 17q23 through long-range chromosome interactions. One of these loci, Tousled Like Kinase 2 (TLK2) known to participate in DNA damage checkpoint control, is an actionable target using phenothiazine antipsychotics (PTZs). The antiproliferative effect of PTZs was prominent in high TLK2-expressing cells, compared to low expressing cells. CONCLUSION: This study demonstrates a new approach for identifying tumorigenic drivers from genomic regions highly susceptible to ERα-related chromothripsis. We found a group of luminal breast tumors displaying 17q-related chromothripsis for which antipsychotics can be repurposed as treatment adjuncts.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Cromosomas Humanos Par 17/genética , Cromotripsis , Receptor alfa de Estrógeno/metabolismo , Regulación Neoplásica de la Expresión Génica , Biomarcadores de Tumor/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Ciclo Celular , Proliferación Celular , Receptor alfa de Estrógeno/genética , Femenino , Humanos , Pronóstico , Tasa de Supervivencia , Transcripción Genética , Células Tumorales Cultivadas , Secuenciación del Exoma , Secuenciación Completa del GenomaRESUMEN
Importance: A high 21-gene recurrence score (RS) by breast cancer assay is prognostic for distant recurrence of early breast cancer after local therapy and endocrine therapy alone, and for chemotherapy benefit. Objective: To describe clinical outcomes for women with a high RS who received adjuvant chemotherapy plus endocrine therapy in the TAILORx trial, a population expected to have a high distant recurrence rate with endocrine therapy alone. Design, Setting, and Participants: In this secondary analysis of data from a multicenter randomized clinical trial, 1389 women with hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer, and a high RS of 26 to 100 were prospectively assigned to receive adjuvant chemotherapy in addition to endocrine therapy. The analysis was conducted on May 12, 2019. Interventions: The adjuvant chemotherapy regimen was selected by the treating physician. Main Outcomes and Measures: Freedom from recurrence of breast cancer at a distant site, and freedom from recurrence, second primary cancer, and death (also known as invasive disease-free survival [IDFS]). Results: Among the 9719 eligible women, with a mean age of 56 years (range 23-75 years), 1389 (14%) had a recurrence score of 26 to 100, of whom 598 (42%) had an RS of 26 to 30 and 791 (58%) had an RS of 31 to 100. The most common chemotherapy regimens included docetaxel/cyclophosphamide in 589 (42%), an anthracycline without a taxane in 334 (24%), an anthracycline and taxane in 244 (18%), cyclophosphamide/methotrexate/5-fluorouracil in 52 (4%), other regimens in 81 (6%), and no chemotherapy in 89 (6%). At 5 years, the estimated rate of freedom from recurrence of breast cancer at a distant site was 93.0% (standard error [SE], 0.8%), freedom of recurrence of breast cancer at a distant and/or local regional site 91.0% (SE, 0.8%), IDFS 87.6% (SE, 1.0%), and overall survival 95.9% (SE, 0.6%). Conclusions and Relevance: The estimated rate of freedom from recurrence of breast cancer at a distant site in women with an RS of 26 to 100 treated largely with taxane and/or anthracycline-containing adjuvant chemotherapy regimens plus endocrine therapy in the prospective TAILORx trial was 93% at 5 years, an outcome better than expected with endocrine therapy alone in this population. Trial Registration: ClinicalTrials.gov identifier: NCT00310180.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Quimioterapia Adyuvante , Recurrencia Local de Neoplasia/genética , Adulto , Anciano , Antraciclinas/uso terapéutico , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Ciclofosfamida/uso terapéutico , Docetaxel/uso terapéutico , Femenino , Fluorouracilo/uso terapéutico , Humanos , Metotrexato/uso terapéutico , Persona de Mediana Edad , Taxoides/uso terapéutico , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Neoadjuvant dual human epidermal growth factor receptor (HER2) blockade with trastuzumab and pertuzumab plus paclitaxel leads to an overall pathologic complete response (pCR) rate of 46%. Dual HER2 blockade with ado-trastuzumab emtansine (T-DM1) and lapatinib plus nab-paclitaxel has shown efficacy in patients with metastatic HER2-positive breast cancer. To test neoadjuvant effectiveness of this regimen, an open-label, multicenter, randomized, phase II trial was conducted comparing T-DM1, lapatinib, and nab-paclitaxel with trastuzumab, pertuzumab, and paclitaxel in patients with early-stage HER2-positive breast cancer. METHODS: Stratification by estrogen receptor (ER) status occurred prior to randomization. Patients in the experimental arm received 6 weeks of targeted therapies (T-DM1 and lapatinib) followed by T-DM1 every 3 weeks, lapatinib daily, and nab-paclitaxel weekly for 12 weeks. In the standard arm, patients received 6 weeks of trastuzumab and pertuzumab followed by trastuzumab weekly, pertuzumab every 3 weeks, and paclitaxel weekly for 12 weeks. The primary objective was to evaluate the proportion of patients with residual cancer burden (RCB) 0 or I. Key secondary objectives included pCR rate, safety, and change in tumor size at 6 weeks. Hypothesis-generating correlative assessments were also performed. RESULTS: The 30 evaluable patients were well-balanced in patient and tumor characteristics. The proportion of patients with RCB 0 or I was higher in the experimental arm (100% vs. 62.5% in the standard arm, p = 0.0035). In the ER-positive subset, all patients in the experimental arm achieved RCB 0-I versus 25% in the standard arm (p = 0.0035). Adverse events were similar between the two arms. CONCLUSION: In early-stage HER2-positive breast cancer, the neoadjuvant treatment with T-DM1, lapatinib, and nab-paclitaxel was more effective than the standard treatment, particularly in the ER-positive cohort. TRIAL REGISTRATION: Clinicaltrials.gov NCT02073487 , February 27, 2014.
Asunto(s)
Ado-Trastuzumab Emtansina/uso terapéutico , Albúminas/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Lapatinib/uso terapéutico , Paclitaxel/uso terapéutico , Receptor ErbB-2/antagonistas & inhibidores , Ado-Trastuzumab Emtansina/administración & dosificación , Ado-Trastuzumab Emtansina/efectos adversos , Adulto , Anciano , Albúminas/administración & dosificación , Albúminas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Lapatinib/administración & dosificación , Lapatinib/efectos adversos , Persona de Mediana Edad , Terapia Neoadyuvante , Paclitaxel/administración & dosificación , Paclitaxel/efectos adversos , Receptor ErbB-2/metabolismo , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacosRESUMEN
Elacestrant is a novel, nonsteroidal, orally bioavailable selective estrogen receptor degrader (SERD) that has demonstrated activity in patients with estrogen receptor (ER)-positive/HER2-negative breast cancer previously treated with endocrine therapies including fulvestrant and/or CDK 4/6 inhibitor therapy, and in those with ESR1 mutations (ESR1-mut) known to confer endocrine resistance. Herein, we describe the design and methodology of EMERALD, an international, multicenter, randomized, open-label, active-controlled, Phase III clinical study comparing the efficacy and safety of elacestrant to standard-of-care endocrine monotherapy treatment (fulvestrant or an aromatase inhibitor, per investigator's choice) in patients with ER-positive/HER2-negative advanced breast cancer. Primary end points are progression-free survival in ESR1-mut patients and in all patients (NCT03778931; EudraCT 2018-002990-24).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Receptor alfa de Estrógeno/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Estudios de Seguimiento , Fulvestrant/administración & dosificación , Humanos , Agencias Internacionales , Persona de Mediana Edad , Pronóstico , Estudios Prospectivos , Tasa de Supervivencia , Tetrahidronaftalenos/administración & dosificaciónRESUMEN
INTRODUCTION: As cancer center funds are allocated toward several resources, clinical trial offices and the clinical trial infrastructure is constantly scrutinized. It has been shown that 20% of clinical trials fail to achieve their accrual goal and in an institutional level several trials are open with poor accrual. We sought to identify factors that are associated with clinical trial accrual and develop a model to predict clinical trial accrual. METHODS AND MATERIAL: We identified all clinical trials from 1999 to 2015â¯at UT Health Cancer Center San Antonio. We included observational as well as interventional clinical trials. We collected several variables such as type of study, type of malignancy, trial phase, PI of study. RESULTS: In total we included 297 clinical trials. We identified several factors to be associated with clinical trial accrual (Sponsor type, trial phase, disease category, type of trial, disease state and whether the trial involved a new investigational agent). We developed a predictive model with an AUC of 0.65 that showed that observational, interventional, industry-sponsored trials and trials authored by the local PI were more likely to achieve their accrual goal. CONCLUSION: We were able to identify several factors that were significantly associated with clinical trial accrual. Based on these factors we developed a prediction model for clinical trial accrual. We believe that use of this model can help improve our cancer centers clinical trial portfolio and help in fund allocation.
RESUMEN
BACKGROUND: The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known. METHODS: We performed a prospective trial involving 9427 women with hormone-receptor-positive, human epidermal growth factor receptor 2-negative, axillary node-negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger. RESULTS: The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%). CONCLUSIONS: Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT00310180.).
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Perfilación de la Expresión Génica , Tamoxifeno/uso terapéutico , Adulto , Factores de Edad , Anciano , Algoritmos , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Antagonistas de Estrógenos/uso terapéutico , Femenino , Humanos , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/prevención & control , Premenopausia , Pronóstico , Modelos de Riesgos Proporcionales , Estudios Prospectivos , Receptor ErbB-2 , Factores de RiesgoRESUMEN
Resistance to endocrine therapy (ET) is common in patients with hormone receptor positive (HR+) advanced breast cancer (ABC). Consequently, new targeted treatment options are needed in the post-ET setting, with validated biomarkers to inform treatment decisions. Hyperactivation of the phosphoinositide 3-kinase (PI3K) signaling pathway is common in ABC and is implicated in resistance to ET. The most frequent mechanism of PI3K pathway activation is activating mutations or amplification of PIK3CA, which encodes the α-isoform of the catalytic subunit of PI3K. Combining buparlisib, a pan-PI3K-targeted agent, with ET demonstrated modest clinical benefits in patients with aromatase inhibitor-resistant, HR+, human epidermal growth receptor 2 negative (HER2-) ABC in two phase III trials. Importantly, greater efficacy gains were observed in individuals with PIK3CA-mutated disease versus PIK3CA-wild-type tumors. Although the challenging safety profile did not support widespread use of this treatment combination, isoform-selective PI3K inhibitors may improve tolerability. In early clinical trials, promising disease control benefits were demonstrated with the PI3K isoform-selective inhibitors alpelisib and taselisib in patients with PIK3CA-mutated HR+, HER2- ABC. Ongoing biomarker-guided phase II/III studies may provide further opportunities to identify patients most likely to benefit from treatment with PI3K inhibitors and provide insight into optimizing the therapeutic index of PI3K inhibitors. Challenges facing the implementation of routine PIK3CA mutation testing must be addressed promptly so robust and reproducible genotyping can be obtained with liquid and tumor biopsies in a timely and cost-effective manner. IMPLICATIONS FOR PRACTICE: The development of phosphoinositide 3-kinase (PI3K) inhibitors, especially those that selectively target isoforms, may be an effective strategy for overcoming endocrine therapy resistance in hormone receptor positive, human epidermal growth receptor 2 negative advanced breast cancer. Early-phase studies have confirmed that patients with PIK3CA mutations respond best to PI3Kα-isoform inhibition. Ongoing phase III trials will provide further data regarding the efficacy and safety of PI3K inhibitors in patients with different biomarker profiles.