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1.
NPJ Breast Cancer ; 6: 37, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32864429

RESUMO

Recurrence of estrogen receptor (ER)-positive breast tumors despite curative-intent adjuvant therapy is thought to be due to enrichment of tumor initiating cells (TIC) during endocrine therapy (ET). Recently, it was identified that by antagonizing the ER, ET promotes rapid degradation of the death-associated factor 6 (DAXX) protein, which is necessary and sufficient to potently inhibit TICs. Thus, the goal of the current study was to identify a DAXX-inducing agent to inhibit TICs and prevent proliferation of the tumor. Phytoestrogens (naringenin, resveratrol, genistein, apigenin, and quercetin) were screened for DAXX protein expression, anti-TIC and anti-proliferative efficacy in vitro and in vivo. Specific DAXX-inducing phytoestrogens were tested to assess selectivity towards ERα and/or ERß. Results showed that phytoestrogens tested induced DAXX protein expression and inhibited survival of TICs from ER+ MCF-7 and T47D cells. Only naringenin, resveratrol, and quercetin did not stimulate total cell proliferation. Naringenin, resveratrol, but not quercetin inhibited survival of TICs in vitro and in vivo in a DAXX-dependent manner. Naringenin-induced DAXX protein expression and inhibition of TICs seemed to be more selective towards ERß while resveratrol was more selective through ERα. Naringenin or resveratrol inhibited the rate of tumor initiation and rate of tumor growth in a DAXX-dependent manner. These results suggest that a therapeutic approach using a phytoestrogen to induce DAXX protein expression could potently inhibit TICs within a tumor to delay or prevent tumor initiation. Therefore, a DAXX-promoting phytoestrogen should be explored for prevention of tumor progression in advanced disease and relapse in the adjuvant setting.

2.
J Natl Cancer Inst ; 2020 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-32986828

RESUMO

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 TAILORx. METHODS: The association between clinical outcomes and race (White, Black, Asian, other/unknown) and ethnicity (Hispanic vs. non-Hispanic) was examined using proportional hazards models. All P values are two-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/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 TAILORx. 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.

3.
JAMA Oncol ; 6(9): 1355-1362, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32701140

RESUMO

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.

4.
J Natl Cancer Inst ; 2020 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-32239145

RESUMO

BACKGROUND: Although physical activity has been consistently associated with reduced breast cancer mortality, evidence is largely based upon data collected at one occasion. We examined how pre- and post-diagnosis physical activity was associated with survival outcomes in high-risk breast cancer patients. METHODS: Included were 1,340 patients enrolled in the DELCaP Study, a prospective study of lifestyle and prognosis ancillary to a SWOG clinical trial (S0221). Activity before diagnosis, during treatment, and at one-and two-year intervals after enrollment were collected. Patients were categorized according to the Physical Activity Guidelines as meeting the minimum Guidelines (yes/no) and incrementally as inactive, low-active, moderately active (meeting the Guidelines), or high-active. RESULTS: In joint-exposure analyses, patients meeting the Guidelines before and one-year after diagnosis experienced statistically significant reductions in hazards of recurrence (HR=0.59, 95% CI: 0.42-0.82) and mortality (HR=0.51, 95% CI: 0.34-0.77); associations were stronger at two-year follow-up for recurrence (HR=0.45, 95% CI: 0.31-0.65) and mortality (HR=0.32, 95% CI: 0.19-0.52). In time-dependent analyses, factoring in activity from all time points, we observed striking associations with mortality for low- (HR = 0.41, 95% CI: 0.24-0.68), moderate- (HR = 0.42, 95% CI: 0.23-0.76), and high-active patients (HR=0.31, 95% CI: 0.18-0.53). CONCLUSIONS: Meeting the minimum Guidelines for physical activity both before diagnosis and after treatment appears to be associated with statistically significantly reduced hazards of recurrence and mortality among breast cancer patients. When considering activity from all time points, including during treatment, lower volumes of regular activity were associated with similar overall survival advantages as meeting and exceeding the Guidelines.

5.
J Clin Oncol ; 38(17): 1875-1886, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32271671

RESUMO

PURPOSE: Cancer-related cognitive impairment (CRCI) is common during adjuvant chemotherapy and may persist. TAILORx provided a novel opportunity to prospectively assess patient-reported cognitive impairment among women with early breast cancer who were randomly assigned to chemoendocrine therapy (CT+E) versus endocrine therapy alone (E), allowing us to quantify the unique contribution of chemotherapy to CRCI. METHODS: Women with a 21-gene recurrence score of 11 to 25 enrolled in TAILORX were randomly assigned to CT+E or E. Cognitive impairment was assessed among a subgroup of 552 evaluable women using the 37-item Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaire, administered at baseline, 3, 6, 12, 24, and 36 months. The FACT-Cog included the 20-item Perceived Cognitive Impairment (PCI) scale, our primary end point. Clinically meaningful changes were defined a priori and linear regression was used to model PCI scores on baseline PCI, treatment, and other factors. RESULTS: FACT-Cog PCI scores were significantly lower, indicating more impairment, at 3, 6, 12, 24, and 36 months compared with baseline for both groups. The magnitude of PCI change scores was greater for CT+E than E at 3 months, the prespecified primary trial end point, and at 6 months, but not at 12, 24, and 36 months. Tests of an interaction between menopausal status and treatment were nonsignificant. CONCLUSION: Adjuvant CT+E is associated with significantly greater CRCI compared with E at 3 and 6 months. These differences abated over time, with no significant differences observed at 12 months and beyond. These findings indicate that chemotherapy produces early, but not sustained, cognitive impairment relative to E, providing reassurance to patients and clinicians in whom adjuvant chemotherapy is indicated to reduce recurrence risk.

6.
J Clin Oncol ; 38(10): 1059-1069, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32031889

RESUMO

PURPOSE: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer. PATIENTS AND METHODS: I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week. RESULTS: MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform). CONCLUSION: The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.

7.
JAMA Oncol ; 6(4): 505-511, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31917424

RESUMO

Importance: The 21-gene assay recurrence score is increasingly used to personalize treatment recommendations for systemic therapy in postmenopausal women with estrogen receptor (ER)- or progesterone receptor (PR)-positive, node-positive breast cancer; however, the relevance of the 21-gene assay to radiotherapy decisions remains uncertain. Objective: To examine the association between recurrence score and locoregional recurrence (LRR) in a postmenopausal patient population treated with adjuvant chemotherapy followed by tamoxifen or tamoxifen alone. Design, Setting, and Participants: This cohort study was a retrospective analysis of the Southwest Oncology Group S8814, a phase 3 randomized clinical trial of postmenopausal women with ER/PR-positive, node-positive breast cancer treated with tamoxifen alone, chemotherapy followed by tamoxifen, or concurrent tamoxifen and chemotherapy. Patients at North American clinical centers were enrolled from June 1989 to July 1995. Medical records from patients with recurrence score information were reviewed for LRR and radiotherapy use. Primary analysis included 316 patients and excluded 37 who received both mastectomy and radiotherapy, 9 who received breast-conserving surgery without documented radiotherapy, and 5 with unknown surgical type. All analyses were performed from January 22, 2016, to August 9, 2019. Main Outcomes and Measures: The LRR was defined as a recurrence in the breast; chest wall; or axillary, infraclavicular, supraclavicular, or internal mammary lymph nodes. Time to LRR was tested with log-rank tests and Cox proportional hazards regression for multivariate models. Results: The final cohort of this study comprised 316 women with a mean (range) age of 60.4 (44-81) years. Median (interquartile range) follow-up for those without LRR was 8.7 (7.0-10.2) years. Seven LRR events (5.8%) among 121 patients with low recurrence score and 27 LRR events (13.8%) among 195 patients with intermediate or high recurrence score occurred. The estimated 10-year cumulative incidence rates were 9.7% for those with a low recurrence score and 16.5% for the group with intermediate or high recurrence score (P = .02). Among patients who had a mastectomy without radiotherapy (n = 252), the differences in the 10-year actuarial LRR rates remained significant: 7.7 % for the low recurrence score group vs 16.8% for the intermediate or high recurrence score group (P = .03). A multivariable model controlling for randomized treatment, number of positive nodes, and surgical type showed that a higher recurrence score was prognostic for LRR (hazard ratio [HR], 2.36; 95% CI, 1.02-5.45; P = .04). In a subset analysis of patients with a mastectomy and 1 to 3 involved nodes who did not receive radiation therapy, the group with a low recurrence score had a 1.5% rate of LRR, whereas the group with an intermediate or high recurrence score had a 11.1% LRR (P = .051). Conclusions and Relevance: This study found that higher recurrence scores were associated with increased LRR after adjustment for treatment, type of surgical procedure, and number of positive nodes. This finding suggests that the recurrence score may be used, along with accepted clinical variables, to assess the risk of LRR during radiotherapy decision-making.

8.
JAMA Oncol ; 6(3): 367-374, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31566680

RESUMO

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.

9.
J Clin Oncol ; 38(8): 804-814, 2020 03 10.
Artigo em Inglês | MEDLINE | ID: mdl-31855498

RESUMO

PURPOSE: Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes. METHODS: Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach. RESULTS: There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes. CONCLUSION: Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.

10.
J Clin Oncol ; 38(5): 444-453, 2020 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-31821109

RESUMO

PURPOSE: Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer. PATIENTS AND METHODS: A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) < 2.0 or, if ratio was not performed, HER2 gene copy number < 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks. RESULTS: At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab [CRxT] v 89.2% with CRx alone; hazard ratio [HR], 0.98; 95% CI, 0.76 to 1.25; P = .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50; P = .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95; P = .15). There were no unexpected toxicities from the addition of trastuzumab to CRx. CONCLUSION: The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2-overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/biossíntese , Antineoplásicos Imunológicos/administração & dosagem , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Docetaxel/administração & dosagem , Doxorrubicina/administração & dosagem , Feminino , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Pessoa de Meia-Idade , Invasividade Neoplásica , Receptor ErbB-2/genética , Fatores de Risco , Trastuzumab/administração & dosagem
11.
Cancer Res ; 79(19): 4965-4977, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31387918

RESUMO

Estrogen receptor (ER)-positive breast cancer recurrence is thought to be driven by tumor-initiating cells (TIC). TICs are enriched by endocrine therapy through NOTCH signaling. Side effects have limited clinical trial testing of NOTCH-targeted therapies. Death-associated factor 6 (DAXX) is a newly identified marker whose RNA expression inversely correlates with NOTCH in human ER+ breast tumor samples. In this study, knockdown and overexpression approaches were used to investigate the role of DAXX on stem/pluripotent gene expression, TIC survival in vitro, and TIC frequency in vivo, and the mechanism by which DAXX suppresses TICs in ER+ breast cancer. 17ß-Estradiol (E2)-mediated ER activation stabilized the DAXX protein, which was required for repressing stem/pluripotent genes (NOTCH4, SOX2, OCT4, NANOG, and ALDH1A1), and TICs in vitro and in vivo. Conversely, endocrine therapy promoted rapid protein depletion due to increased proteasome activity. DAXX was enriched at promoters of stem/pluripotent genes, which was lost with endocrine therapy. Ectopic expression of DAXX decreased stem/pluripotent gene transcripts to levels similar to E2 treatment. DAXX-mediated repression of stem/pluripotent genes and suppression of TICs was dependent on DNMT1. DAXX or DNMT1 was necessary to inhibit methylation of CpGs within the SOX2 promoter and moderately within the gene body of NOTCH4, NOTCH activation, and TIC survival. E2-mediated stabilization of DAXX was necessary and sufficient to repress stem/pluripotent genes by recruiting DNMT1 to methylate some promoters and suppress TICs. These findings suggest that a combination of endocrine therapy and DAXX-stabilizing agents may inhibit ER+ tumor recurrence. SIGNIFICANCE: Estradiol-mediated stabilization of DAXX is necessary and sufficient to repress genes associated with stemness, suggesting that the combination of endocrine therapy and DAXX-stabilizing agents may inhibit tumor recurrence in ER+ breast cancer.


Assuntos
Neoplasias da Mama/patologia , Proteínas Correpressoras/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Chaperonas Moleculares/metabolismo , Recidiva Local de Neoplasia/patologia , Células-Tronco Neoplásicas/metabolismo , Animais , Antineoplásicos Hormonais/farmacologia , Feminino , Xenoenxertos , Humanos , Camundongos , Camundongos Nus , Recidiva Local de Neoplasia/metabolismo , Células-Tronco Neoplásicas/patologia , Receptores Estrogênicos/metabolismo
12.
J Thorac Oncol ; 14(10): 1853-1859, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31302234

RESUMO

OBJECTIVE: Lung-MAP (SWOG S1400) is a master platform trial assessing targeted therapies in squamous NSCLC. The objective of study C (S1400C) was to evaluate the response rate to palbociclib, a cyclin-dependent kinase 4 and cyclin-dependent kinase 6 inhibitor, in patients with cell cycle gene abnormalities. METHODS: Patients with squamous NSCLC, a performance status of 0 to 2, and normal organ function who had progressed after at least one prior platinum-based chemotherapy with cyclin-dependent kinase 4 gene (CDK4) or cyclin D1 gene (CCND1), cyclin D2 gene (CCND2), or cyclin D3 gene (CCND3) amplifications on tumor specimens were eligible. The study was originally designed as a phase II/III trial comparing palbociclib with docetaxel, but it was modified to a single-arm phase II trial with the primary end point of response when immunotherapy was approved. If two or fewer responses were seen in the first 20 patients, then the study would cease enrollment. RESULTS: A total of 88 patients (9% of patients screened) were assigned to S1400C, and 53 patients enrolled (including 17 to receive docetaxel). One patient who had been registered to receive docetaxel was re-registered to receive palbociclib after progression while taking docetaxel. The frequencies of cell cycle gene alterations in the eligible patients taking palbociclib (n = 32) were as follows: CCND1, 81% (n = 26); CCND2, 9% (n = 3); CCND3, 6% (n = 2); and CDK4, 3% (n = 1). In all, 32 eligible patients received palbociclib. There were two partial responses (response rate 6% [95% confidence interval (CI): 0%-15%]), both with CCND1 amplification. Twelve patients had stable disease (38% [95% CI: 21%-54%]). The median progression-free survival was 1.7 months (95% CI: 1.6-2.9 months) and the median overall survival was 7.1 months (95% CI: 4.2-12.5). CONCLUSION: Palbociclib as monotherapy failed to demonstrate the prespecified criteria for advancement to phase III testing.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Proteínas de Ciclo Celular/genética , Neoplasias Pulmonares/tratamento farmacológico , Mutação , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Terapia de Salvação , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/genética , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/genética , Neoplasias Ósseas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Amplificação de Genes , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Taxa de Sobrevida
13.
N Engl J Med ; 380(25): 2395-2405, 2019 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-31157962

RESUMO

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.).


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Perfilação da Expressão Gênica , Tamoxifeno/uso terapêutico , Adulto , Fatores Etários , Idoso , Algoritmos , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Intervalo Livre de Doença , Antagonistas de Estrogênios/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/prevenção & controle , Pré-Menopausa , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Receptor ErbB-2 , Fatores de Risco
14.
J Clin Oncol ; 37(22): 1868-1875, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939096

RESUMO

PURPOSE: The Adjuvant Paclitaxel and Trastuzumab trial was designed to address treatment of patients with small human epidermal growth factor receptor 2 (HER2)-positive breast cancer. The primary analysis of the Adjuvant Paclitaxel and Trastuzumab trial demonstrated a 3-year disease-free survival (DFS) of 98.7%. In this planned secondary analysis, we report longer-term outcomes and exploratory results to characterize the biology of small HER2-positive tumors and genetic factors that may predispose to paclitaxel-induced peripheral neuropathy (TIPN). PATIENTS AND METHODS: In this phase II study, patients with HER2-positive breast cancer with tumors 3 cm or smaller and negative nodes received paclitaxel (80 mg/m2) with trastuzumab for 12 weeks, followed by trastuzumab for 9 months. The primary end point was DFS. Recurrence-free interval (RFI), breast cancer-specific survival, and overall survival (OS) were also analyzed. In an exploratory analysis, intrinsic subtyping by PAM50 (Prosigna) and calculation of the risk of recurrence score were performed on the nCounter analysis system on archival tissue. Genotyping was performed to investigate TIPN. RESULTS: A total of 410 patients were enrolled from October 2007 to September 2010. After a median follow-up of 6.5 years, there were 23 DFS events. The 7-year DFS was 93% (95% CI, 90.4 to 96.2) with four (1.0%) distant recurrences, 7-year OS was 95% (95% CI, 92.4 to 97.7), and 7-year RFI was 97.5% (95% CI, 95.9 to 99.1). PAM50 analyses (n = 278) showed that most tumors were HER2-enriched (66%), followed by luminal B (14%), luminal A (13%), and basal-like (8%). Genotyping (n = 230) identified one single-nucleotide polymorphism, rs3012437, associated with an increased risk of TIPN in patients with grade 2 or greater TIPN (10.4%). CONCLUSION: With longer follow-up, adjuvant paclitaxel and trastuzumab is associated with excellent long-term outcomes. Distribution of PAM50 intrinsic subtypes in small HER2-positive tumors is similar to that previously reported for larger tumors.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Regulação Neoplásica da Expressão Gênica , Paclitaxel/administração & dosagem , Receptor ErbB-2/genética , Trastuzumab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/genética , Neoplasias da Mama Masculina/tratamento farmacológico , Neoplasias da Mama Masculina/genética , Quimioterapia Adjuvante , Intervalo Livre de Doença , Feminino , Seguimentos , Predisposição Genética para Doença , Genótipo , Humanos , Linfonodos/patologia , Masculino , Pessoa de Meia-Idade , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Distribuição de Poisson , Polimorfismo de Nucleotídeo Único , Recidiva , Risco , Trastuzumab/efeitos adversos , Resultado do Tratamento
15.
Breast Cancer Res Treat ; 176(2): 303-310, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31004299

RESUMO

PURPOSE: Women with HER2-positive breast cancer treated prior to effective anti-HER2 therapy have higher rates of local-regional recurrence (LRR) than those with HER2-negative disease. Effective systemic therapy, however, has been shown to decrease LRR. This study examines LRR in women with HER2-positive breast cancer treated on a single-arm prospective multicenter trial of adjuvant trastuzumab (H) and paclitaxel (T). METHODS: Patients with HER2-positive tumors ≤ 3.0 cm with negative axillary nodes or micrometastatic disease were eligible. Systemic therapy included weekly T and H for 12 weeks followed by continuation of H to complete 1 year. Radiation therapy (RT) was required following breast-conserving surgery (BCS), but dose and fields were not specified. Disease-free survival (DFS) and LRR-free survival were calculated using the Kaplan-Meier method. RESULTS: Of the 410 patients enrolled from September 2007 to September 2010, 406 initiated protocol therapy and formed the basis of this analysis. A total of 272 (67%) had hormone receptor-positive tumors. Of 162 patients undergoing mastectomy, local therapy records were unavailable for two. None of the 160 for whom records were available received RT. Among 244 BCS patients, detailed RT records were available for 217 (89%). With a median follow-up of 6.5 years, 7-year DFS was 93.3% (95% CI 90.4-96.2), and LRR-free survival was 98.6% (95% CI 97.4-99.8). CONCLUSION: LRR in this select group of early-stage patients with HER2-positive disease receiving effective anti-HER2 therapy is extremely low. If confirmed in additional studies, future investigational efforts should focus on de-escalating local therapy.


Assuntos
Neoplasias da Mama/terapia , Recidiva Local de Neoplasia/epidemiologia , Paclitaxel/administração & dosagem , Receptor ErbB-2/metabolismo , Trastuzumab/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Feminino , Humanos , Metástase Linfática , Mastectomia Segmentar , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Paclitaxel/uso terapêutico , Estudos Prospectivos , Radioterapia Adjuvante , Receptor ErbB-2/antagonistas & inibidores , Análise de Sobrevida , Trastuzumab/farmacologia , Resultado do Tratamento
16.
Clin Breast Cancer ; 19(4): 225-235.e2, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30928413

RESUMO

INTRODUCTION: GATA3 is a critical transcription factor in maintaining the differentiated state of luminal mammary epithelial cells. We sought to determine the prognostic and predictive roles of GATA3 genotypes for breast cancer. PATIENTS AND METHODS: Twelve single nucleotide polymorphisms (SNPs) were genotyped in 2 breast cancer cohorts, including the SWOG S8897 trial where patients were treated with adjuvant chemotherapy (CAF [cyclophosphamide, doxorubicin, 5-fluorouracil] vs. CMF [cyclophosphamide, methotrexate, 5-fluorouracil]) or untreated, and the observational Pathways Study. RESULTS: In the S8897 trial, rs3802604 and rs568727 were associated with disease-free survival and overall survival in the treated group, regardless of chemotherapy regimen. The GG genotype of rs3802604 conferred poorer overall survival (adjusted hazard ratio, 2.45; 95% confidence interval, 1.48-4.05) and disease-free survival (adjusted hazard ratio, 1.95; 95% confidence interval, 1.27-2.99) compared with the AA genotype. Similar associations were found for rs568727. In contrast, no association with either SNP was found in the untreated group. Subgroup analyses indicated that these 2 SNPs more strongly influenced outcomes in the patients who also received tamoxifen. However, the associations in the subgroup with tamoxifen treatment were not replicated in the Pathways Study, possibly owing to substantial differences between the 2 patient cohorts, such as chemotherapy regimen and length of follow-up. Results from joint analyses across these 2 cohorts were marginally significant, driven by the results in S8897. Bioinformatic analyses support potential functional disruption of the GATA3 SNPs in breast tissue. CONCLUSIONS: The present study provides some evidence for the predictive value of GATA3 genotypes for breast cancer adjuvant therapies. Future replication studies in appropriate patient populations are warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/mortalidade , Fator de Transcrição GATA3/genética , Mutação em Linhagem Germinativa , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida
17.
N Engl J Med ; 380(13): 1226-1234, 2019 03 28.
Artigo em Inglês | MEDLINE | ID: mdl-30917258

RESUMO

BACKGROUND: We previously reported prolonged progression-free survival and marginally prolonged overall survival among postmenopausal patients with hormone receptor-positive metastatic breast cancer who had been randomly assigned to receive the aromatase inhibitor anastrozole plus the selective estrogen-receptor down-regulator fulvestrant, as compared with anastrozole alone, as first-line therapy. We now report final survival outcomes. METHODS: We randomly assigned patients to receive either anastrozole or fulvestrant plus anastrozole. Randomization was stratified according to adjuvant tamoxifen use. Analysis of survival was performed by means of two-sided stratified log-rank tests and Cox regression. Efficacy and safety were compared between the two groups, both overall and in subgroups. RESULTS: Of 707 patients who had undergone randomization, 694 had data available for analysis. The combination-therapy group had 247 deaths among 349 women (71%) and a median overall survival of 49.8 months, as compared with 261 deaths among 345 women (76%) and a median overall survival of 42.0 months in the anastrozole-alone group, a significant difference (hazard ratio for death, 0.82; 95% confidence interval [CI], 0.69 to 0.98; P = 0.03 by the log-rank test). In a subgroup analysis of the two strata, overall survival among women who had not received tamoxifen previously was longer with the combination therapy than with anastrozole alone (median, 52.2 months and 40.3 months, respectively; hazard ratio, 0.73; 95% CI, 0.58 to 0.92); among women who had received tamoxifen previously, overall survival was similar in the two groups (median, 48.2 months and 43.5 months, respectively; hazard ratio, 0.97; 95% CI, 0.74 to 1.27) (P = 0.09 for interaction). The incidence of long-term toxic effects of grade 3 to 5 was similar in the two groups. Approximately 45% of the patients in the anastrozole-alone group crossed over to receive fulvestrant. CONCLUSIONS: The addition of fulvestrant to anastrozole was associated with increased long-term survival as compared with anastrozole alone, despite substantial crossover to fulvestrant after progression during therapy with anastrozole alone. The results suggest that the benefit was particularly notable in patients without previous exposure to adjuvant endocrine therapy. (Funded by the National Cancer Institute and AstraZeneca; ClinicalTrials.gov number, NCT00075764.).


Assuntos
Anastrozol/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Antagonistas do Receptor de Estrogênio/administração & dosagem , Fulvestranto/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastrozol/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estudos Cross-Over , Feminino , Seguimentos , Fulvestranto/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Pessoa de Meia-Idade , Metástase Neoplásica/tratamento farmacológico , Pós-Menopausa , Intervalo Livre de Progressão
18.
J Natl Cancer Inst ; 111(2): 210-213, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30371800

RESUMO

Premature menopause is a serious long-term side effect of chemotherapy. We evaluated long-term pregnancy and disease-related outcomes for patients in S0230/POEMS, a study in premenopausal women with stage I-IIIA estrogen receptor-negative, progesterone receptor-negative breast cancer to be treated with cyclophosphamide-containing chemotherapy. Women were randomly assigned to standard chemotherapy with or without goserelin, a gonadotropin-releasing hormone agonist, and were stratified by age and chemotherapy regimen. All statistical tests were two-sided. Of 257 patients, 218 were eligible and evaluable (105 in the chemotherapy + goserelin arm and 113 in the chemotherapy arm). More patients in the chemotherapy + goserelin arm reported at least one pregnancy vs the chemotherapy arm (5-year cumulative incidence = 23.1%, 95% confidence interval [CI] = 15.3% to 31.9%; and 12.2%, 95% CI = 6.8% to 19.2%, respectively; odds ratio = 2.34; 95% CI = 1.07 to 5.11; P = .03). Randomization to goserelin + chemotherapy was associated with a nonstatistically significant improvement in disease-free survival (hazard ratio [HR] = 0.55; 95% CI = 0.27 to 1.10; P = .09) and overall survival (HR = 0.45; 95% CI = 0.19 to 1.04; P = .06). In this long-term analysis of POEMS/S0230, we found continued evidence that patients randomly assigned to receive goserelin + chemotherapy were not only more likely to avoid premature menopause, but were also more likely to become pregnant without adverse effect on disease-related outcomes.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Menopausa Precoce/efeitos dos fármacos , Insuficiência Ovariana Primária/prevenção & controle , Adulto , Antraciclinas/administração & dosagem , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Feminino , Seguimentos , Gosserrelina/administração & dosagem , Humanos , Pessoa de Meia-Idade , Gravidez , Resultado da Gravidez , Receptores Estrogênicos/metabolismo , Taxa de Sobrevida
19.
Breast Cancer Res ; 20(1): 146, 2018 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-30486865

RESUMO

BACKGROUND: The pathophysiology of chemotherapy-induced peripheral neuropathy (CIPN) is not well understood. Currently, dose reduction is the only recommendation for alleviating symptoms, often leading to premature treatment cessation. The primary aim of this analysis was to determine the association between components of diet during taxane treatment for breast cancer and change in CIPN symptoms over treatment. METHODS: Women with stage II or III invasive breast cancer were enrolled into an ancillary study to the North American Breast Cancer Intergroup phase III trial (S0221) led by the Southwest Oncology Group (SWOG). Questionnaires including a food frequency questionnaire and the Functional Assessment of Cancer Treatment Gynecologic Oncology Group-Neurotoxicity were administered to assess diet and neuropathic conditions at baseline and during chemotherapy. Ordinal regression was used to estimate odds ratios (ORs) for associations between various food groups and change in neuropathy score (< 10%, 10-30%, > 30%) (n = 900). RESULTS: The odds of worse neuropathy decreased by 21% for each increase in tertile of grain consumption (OR = 0.79, 95% CI 0.66-0.94, p = 0.009). We also observed a nominal 19% increase with higher consumption of citrus fruits (OR = 1.19, 95% CI 1.01-1.40, p = 0.05). CONCLUSIONS: Distinguishing between those who experienced a moderate and a severe change in neuropathy, we found that citrus fruit and grain consumption may play a role in the severity of symptoms. Since there are no existing dietary recommendations for the management of CIPN, further research is needed to investigate whether there may be certain foods that could worsen or alleviate neuropathy symptoms associated with treatment for breast cancer. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03413761 . Registered retrospectively on 29 January 2018.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Dieta/estatística & dados numéricos , Doenças do Sistema Nervoso Periférico/epidemiologia , Taxoides/efeitos adversos , Adulto , Feminino , Humanos , Pessoa de Meia-Idade , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/dietoterapia , Doenças do Sistema Nervoso Periférico/prevenção & controle , Qualidade de Vida , Autorrelato/estatística & dados numéricos
20.
NPJ Breast Cancer ; 4: 27, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30155517

RESUMO

In contemporary management of early-stage breast cancer, clinical decisions regarding adjuvant systemic therapy are increasingly made after considering both genomic assay results and clinico-pathologic features. Genomic information augments the prognostic information gleaned from clinico-pathologic features by providing risk estimates for distant recurrence and/or breast cancer-specific survival based on individual tumor biology. The 21-gene Oncotype DX Breast Recurrence Score® (RS) assay is validated to be prognostic and predictive of chemotherapy benefit in patients with hormone receptor-positive (HR+), HER2-negative early-stage breast cancer, regardless of nodal status. Because patients frequently are recommended to receive adjuvant chemotherapy based on the perceived poor prognosis related to a positive nodal status, inconsistent use of any prognostic genomic assay in the node-positive (N+) setting likely results in overtreatment of some patients, particularly those with a low genomic risk as defined by the RS test. This comprehensive review of the evidence for the RS assay in patients with N+, HR+, HER2-negative early-stage breast cancer focuses on outcomes of patients with low RS results treated with hormonal therapy alone. Aggregate findings show that the RS assay consistently identifies patients with low genomic risk N+ breast cancer, in whom adjuvant chemotherapy can be avoided without adversely affecting outcomes. This evidence suggests that HR+ patients with limited nodal involvement and low RS results should discuss with their physicians the pros and cons of adjuvant chemotherapy at the time their treatment plans are being decided.

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