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1.
Cancers (Basel) ; 12(11)2020 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-33114311

RESUMO

The AJCC updated its breast cancer staging system to incorporate biological factors in the "prognostic stage". We undertook this study to validate the prognostic and anatomic stages for inflammatory breast cancer (IBC). We established two cohorts of IBC diagnosed without distant metastasis: (1) patients treated at The University of Texas MD Anderson Cancer Center between 1991 and 2017 (MDA cohort) and (2) patients registered in the national Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015 (SEER cohort). For prognostic staging, estrogen receptor (ER)+/progesterone receptor (PR)+/ human epidermal growth factor receptor-2 (HER2)+/grade 1-2 was staged as IIIA; ER+/PR-/HER2-/grade 3, ER-/PR+/HER2-/grade 3, and triple-negative cancers as IIIC; and all others as IIIB. Endpoints were breast cancer-specific survival (BCSS), overall survival (OS), and disease-free survival (DFS). We studied 885 patients in the MDA cohort and 338 in the SEER cohort. In the MDA cohort, the prognostic stage showed significant predictive power for BCSS, OS, and DFS (all p < 0.0001), although the anatomic stage did not. In both cohorts, the Harrell concordance index (C index) was significantly higher in the prognostic stage than the anatomic stage for all endpoints. In conclusion, the prognostic stage provided more accurate prognostication for IBC than the anatomic stage. Our results show that the prognostic staging is applicable in IBC.

2.
Support Care Cancer ; 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32929540

RESUMO

PURPOSE: Bisphosphonates reduce bone metastases in postmenopausal women with early-stage breast cancer but carry the risk of bisphosphonate-related osteonecrosis of the jaw (BRONJ). We describe risk factors for BRONJ and compare BRONJ provoked by infection or trauma with spontaneous lesions, which carry a better prognosis. METHODS: SWOG 0307 randomized women with stage I-III breast cancer to receive zoledronic acid (ZA), clodronate (CL), or ibandronate (IB) for 3 years, implemented BRONJ prevention guidelines, and collected information about dental health and development of BRONJ. All statistical tests were two-sided. RESULTS: Of 6018 women, 48 developed BRONJ. Infection was present in 21 (43.8%). Median time to BRONJ was 2.1 years for ZA, 2.0 years for IB, and 3.4 years for clodronate (p = 0.04). BRONJ was associated with bisphosphonate type (28/2231 (1.26%) for ZA, 8/2235 (0.36%) for CL, 12/1552 (0.77%) for IB), dental calculus (OR 2.03), gingivitis (OR 2.11), moderate/severe periodontal disease (OR 2.87), and periodontitis > 4 mm (OR 2.20) (p < 0.05). Of 57 lesions, BRONJ occurred spontaneously in 20 (35.1%) and was provoked by dental extraction in 20 (35.1%), periodontal disease in 14 (24.6%), denture trauma in 6 (10.5%), and dental surgery in 2 (3.5%). Spontaneous BRONJ occurred more frequently at the mylohyoid ridge. There were no differences in dental disease, infection, or bisphosphonate type between spontaneous and provoked BRONJ. CONCLUSION: ZA and worse dental health were associated with increased incidence of BRONJ, with a trend toward additive risk when combined. BRONJ incidence was lower than in similar studies, with prevention strategies likely linked to this. CLINICAL TRIAL NUMBER: NCT00127205 REGISTRATION DATE: July 2005.

3.
Front Oncol ; 10: 1197, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32775303

RESUMO

Immune checkpoint inhibitors (ICIs) targeting immune checkpoint proteins, such as CTLA-4 and PD-1/PD-L1, have demonstrated remarkable and durable clinical responses in various cancer types. However, a considerable number of patients receiving ICIs eventually experience a relapse due to diverse resistance mechanisms. As a result, there have been increasing research efforts to elucidate the molecular mechanisms behind resistance to ICIs and improve patient outcomes. There is growing evidence that the dysregulated metabolic activity of tumor cells generates an immunosuppressive tumor microenvironment (TME) that orchestrates an impaired anti-tumor immune response. Notably, the immunosuppressive TME is characterized by nutrient shortage, hypoxia, an acidic extracellular milieu, and abundant immunosuppressive molecules. A detailed understanding of the TME remains a major challenge in mounting a more effective anti-tumor immune response. Herein, we discuss how tumor cells reprogram metabolism to modulate a pro-tumor TME, driving disease progression and immune evasion; in particular, we highlight potential approaches to target metabolic vulnerabilities in the context of anti-tumor immunotherapy.

4.
Oncologist ; 25(9): 749-757, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32431013

RESUMO

BACKGROUND: Delays in the initiation of therapy among patients with early stage breast cancer (BC) can negatively affect outcomes. Patients treated with neoadjuvant systemic chemotherapy (NSC) usually display tumors with high-risk features. Considering these high-risk characteristics and the evidence supporting adverse outcomes associated with delays in adjuvant chemotherapy initiation, we sought to determine whether a delay in NSC initiation is associated with overall survival (OS). METHODS: We identified patients diagnosed between January 1995 and December 2015 with invasive primary BC (stage I-III) who received NSC at MD Anderson Cancer Center. Patients were categorized according to their time from BC diagnosis to NSC (in days) into three subgroups: 0-30, 31-60, and ≥61 days. Primary endpoint was OS. Descriptive statistics and Cox's proportional hazard models were used. RESULTS: A total of 5,137 patients were included. Median follow-up was 6.5 years. The 5-year OS estimates according to time to NSC were 87%, 85%, and 83% in patients who received NSC within 0-30, 31-60, and ≥61 days after diagnosis, respectively (p = .006). In multivariable analysis, compared with time to NSC of 0-30 days, delayed NSC ≥61 days was associated with an increased risk of death (31-60 days: hazard ratio [HR] = 1.05 [95% confidence interval (CI) 0.92-1.19]; ≥61 days, HR = 1.28 [95% CI 1.06-1.54]). In stratified analyses, the association between delay in NSC initiation and increased risk of death was statistically significant for patients with stage I and II BC (31-60 days: HR = 1.22 [95% CI 1.02-1.47]; ≥61 days, HR = 1.41 [95% CI 1.07-1.86]) and among patients with HER2-positive tumors ( ≥61 days, HR = 1.86 [95% CI 1.21-2.86]). CONCLUSION: A delay in NSC initiation of more than 61 days after BC diagnosis was associated with an increased risk of death. Early initiation of NSC should be a priority; multidisciplinary teams must focus on coordination of care and patient-centered, timely treatment planning and delivery. IMPLICATIONS FOR PRACTICE: The results of this study showed that a delay in neoadjuvant systemic chemotherapy initiation of more than 61 days after breast cancer diagnosis is associated with an increased risk of death; therefore, efforts must focus on early initiation of therapy, which should be a priority. Multidisciplinary teams must enhance coordination of care and patient-centered, timely treatment planning and delivery.

5.
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.

6.
J Clin Oncol ; 38(21): 2454-2462, 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32255711
7.
Am J Cancer Res ; 10(2): 648-661, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32195033

RESUMO

The limited treatment options and therapeutic failure due to acquired resistance for patients with triple-negative breast cancer (TNBC) represent a significant challenge. Inhibitors against poly (ADP-ribose) polymerase (PARP), olaparib and talazoparib, were recently approved for the treatment of metastatic breast cancer (including TNBC) in patients with germline BRCA1/2 mutations. Despite impressive response rates of ~60%, the prolongation in median progression-free survival with a PARPi is modest, suggesting the emergence of resistance. Several studies have reported that receptor tyrosine kinases (RTKs), such as c-MET (also known as hepatocyte growth factor receptor), are involved in resistance to various anti-neoplastic agents, including PARPi. However, the mechanism by which c-MET contributes to acquired resistance to PARPi in TNBC is not fully understood. In this study, we show that hyperactivated c-Met is detected in TNBC cells with acquired resistance to PARPi, and the combination of talazoparib and crizotinib (a multi-kinase inhibitor that inhibits c-MET) synergistically inhibits proliferation in these cells. Unexpectedly, depleting c-MET had limited effect on talazoparib sensitivity in PARPi-resistant cells. Interestingly, we found evidence of epidermal growth factor receptor (EGFR) hyperactivation and interaction of EGFR/c-Met in these cells. Notably, combining EGFR and PARP inhibitors resulted in greater inhibition of proliferation in c-MET-depleted TNBC cells, and combined c-MET and EGFR inhibition increased sensitivity to talazoparib in TNBC cells with acquired resistance to PARPi. Our findings suggest that combined inhibition of c-MET and EGFR could potentially re-sensitize TNBC to the cytotoxic effects of PARPi.

8.
NPJ Breast Cancer ; 6: 11, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32219153

RESUMO

We developed prognostic models for breast cancer-specific survival (BCSS) that consider anatomic stage and other important determinants of prognosis and survival in breast cancer, such as age, grade, and receptor-based subtypes with the intention to demonstrate that these factors, conditional on stage, improve prediction of BCSS. A total of 20,928 patients with stage I-III invasive primary breast cancer treated at The University of Texas MD Anderson Cancer Center between 1990 and 2016, who received surgery as an initial treatment were identified to generate prognostic models by Fine-Gray competing risk regression model. Model predictive accuracy was assessed using Harrell's C-index. The Aalen-Johansen estimator and a selected Fine-Gray model were used to estimate the 5-year and 10-year BCSS probabilities. The performance of the selected model was evaluated by assessing discrimination and prediction calibration in an external validation dataset of 29,727 patients from the National Comprehensive Cancer Network (NCCN). The inclusion of age, grade, and receptor-based subtype in addition to stage significantly improved the model predictive accuracy (C-index: 0.774 (95% CI 0.755-0.794) vs. 0.692 for stage alone, p < 0.0001). Young age (<40), higher grade, and TNBC subtype were significantly associated with worse BCSS. The selected model showed good discriminative ability but poor calibration when applied to the validation data. After recalibration, the predictions showed good calibration in the training and validation data. More refined BCSS prediction is possible through a model that has been externally validated and includes clinical and biological factors.

9.
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.

11.
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.

12.
Cancer Med ; 9(3): 1025-1032, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31849202

RESUMO

BACKGROUND: Radium-223 dichloride (Ra-223) is a targeted alpha therapy that induces localized cytotoxicity in bone metastases. We evaluated the efficacy and safety of Ra-223 plus hormonal therapy in hormone receptor-positive (HR+), bone-dominant metastatic breast cancer. METHODS: In this single-center phase II study, 36 patients received Ra-223 (55 kBq/kg intravenously every 4 weeks) up to 6 cycles with endocrine therapy. The primary objective was to determine the clinical disease control rate at 9 months. Secondary objectives were to determine (a) tumor response rate at 6 months, (b) progression-free survival (PFS) durations, and (c) safety. RESULTS: The median number of prior systemic treatments for metastatic disease was 1 (range, 0-4). The disease control rate at 9 months was 49%. The tumor response rate at 6 months was 54% (complete response, 21%; partial, 32%). The median PFS was 7.4 months (95% CI, 4.8-not reached [NR]). The median bone-PFS was 16 months (95% CI, 7.3-NR). There were no grade 3/4 adverse events. CONCLUSIONS: Ra-223 with hormonal therapy showed possible efficacy in HR+ bone-dominant breast cancer metastasis, and adverse events were tolerable. We plan to further investigate the clinical application of Ra-223 in these patients. (NCT02366130).

13.
J Natl Cancer Inst ; 112(7): 698-707, 2020 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31693129

RESUMO

BACKGROUND: Adjuvant bisphosphonates, when given in a low-estrogen environment, can decrease breast cancer recurrence and death. Treatment guidelines include recommendations for adjuvant bisphosphonates in postmenopausal patients. SWOG/Alliance/Canadian Cancer Trials Group/ECOG-ACRIN/NRG Oncology study S0307 compared the efficacy of three bisphosphonates in early-stage breast cancer. METHODS: Patients with stage I-III breast cancer were randomly assigned to 3 years of intravenous zoledronic acid, oral clodronate, or oral ibandronate. The primary endpoint was disease-free survival (DFS) with overall survival as a secondary outcome. All statistical tests were two-sided. RESULTS: A total of 6097 patients enrolled. Median age was 52.7 years. Prior to being randomly assigned, 73.2% patients indicated preference for oral vs intravenous formulation. DFS did not differ across arms in a log-rank test (P = .49); 5-year DFS was 88.3% (zoledronic acid: 95% confidence interval [CI] = 86.9% to 89.6%), 87.6% (clodronate: 95% CI = 86.1% to 88.9%), and 87.4% (ibandronate: 95% CI = 85.6% to 88.9%). Additionally, 5-year overall survival did not differ between arms (log rank P = .50) and was 92.6% (zoledronic acid: 95% CI = 91.4% to 93.6%), 92.4% (clodronate: 95% CI = 91.2% to 93.5%), and 92.9% (ibandronate: 95% CI = 91.5% to 94.1%). Bone as first site of recurrence did not differ between arms (P = .93). Analyses based on age and tumor subtypes showed no treatment differences. Grade 3/4 toxicity was 8.8% (zoledronic acid), 8.3% (clodronate), and 10.5% (ibandronate). Osteonecrosis of the jaw was highest for zoledronic acid (1.26%) compared with clodronate (0.36%) and ibandronate (0.77%). CONCLUSIONS: We found no evidence of differences in efficacy by type of bisphosphonate, either in overall analysis or subgroups. Despite an increased rate of osteonecrosis of the jaw with zoledronic acid, overall toxicity grade differed little across arms. Given that patients expressed preference for oral formulation, efforts to make oral agents available in the United States should be considered.

14.
Genes Cancer ; 10(5-6): 109-118, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31798764

RESUMO

Dr. John Mendelsohn is credited for the concept of targeting the epidermal growth factor receptor (EGFR), providing the first evidence of anticancer activity of antagonist anti-EGFR mAb, and developing the Erbitux (Cetuximab) drug for cancer patients. During his professional journey, Dr. Mendelsohn also helped to build and elevate the status of three cancer cancers, all while touching the lives of cancer patients around the globe. He was a towering figure, and his passing in January 2019 casts a very long shadow over the entire field of cancer research and treatment. Although no one person can ever adequately fill John Mendelsohn's very large shoes, we can all learn by his remarkable example. Here we discuss Dr. Mendelsohn's professional life to spotlight his influence on oncology and also share personal reflections from us and several colleagues: Tony Hunter, Robert A. Weinberg, Robert C. Bast, Raymond Sawaya, David M. Gershenson, Christopher J Logothetis, Stanley R. Hamilton, Mien-Chie Hung, and George M. Stancel. See related article Kumar et al. Can Res 2019; 79:4315-4323.

15.
Nat Commun ; 10(1): 5114, 2019 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-31704972

RESUMO

Triple-negative breast cancer (TNBC), which lacks estrogen receptor α (ERα), progesterone receptor, and human epidermal growth factor receptor 2 (HER2) expression, is closely related to basal-like breast cancer. Previously, we and others report that cyclin E/cyclin-dependent kinase 2 (CDK2) phosphorylates enhancer of zeste homolog 2 (EZH2) at T416 (pT416-EZH2). Here, we show that transgenic expression of phospho-mimicking EZH2 mutant EZH2T416D in mammary glands leads to tumors with TNBC phenotype. Coexpression of EZH2T416D in mammary epithelia of HER2/Neu transgenic mice reprograms HER2-driven luminal tumors into basal-like tumors. Pharmacological inhibition of CDK2 or EZH2 allows re-expression of ERα and converts TNBC to luminal ERα-positive, rendering TNBC cells targetable by tamoxifen. Furthermore, the combination of either CDK2 or EZH2 inhibitor with tamoxifen effectively suppresses tumor growth and markedly improves the survival of the mice bearing TNBC tumors, suggesting that the mechanism-based combination therapy may be an alternative approach to treat TNBC.


Assuntos
Quinase 2 Dependente de Ciclina/metabolismo , Proteína Potenciadora do Homólogo 2 de Zeste/genética , Receptor alfa de Estrogênio/efeitos dos fármacos , Neoplasias Mamárias Experimentais/genética , Neoplasias de Mama Triplo Negativas/genética , Animais , Benzamidas/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/antagonistas & inibidores , Proteína Potenciadora do Homólogo 2 de Zeste/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Glândulas Mamárias Humanas/efeitos dos fármacos , Glândulas Mamárias Humanas/metabolismo , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Camundongos Transgênicos , Fosforilação , Compostos de Piridínio/farmacologia , Piridonas/farmacologia , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo
16.
J Clin Oncol ; 37(36): 3484-3492, 2019 12 20.
Artigo em Inglês | MEDLINE | ID: mdl-31657982

RESUMO

PURPOSE: To independently validate two biomarkers, a 44-gene DNA damage immune response (DDIR) signature and stromal tumor-infiltrating lymphocytes (sTILs), as prognostic markers in patients with triple-negative breast cancer (TNBC) treated with adjuvant doxorubicin (A) and cyclophosphamide (C) in SWOG 9313. METHODS: Four hundred twenty-five centrally determined patient cases with TNBC from S9313 were identified. DDIR signature was performed on RNA isolated from formalin-fixed paraffin-embedded tumor tissue, and samples were classified as DDIR negative or positive using predefined cutoffs. Evaluation of sTILs was performed as described previously. Markers were tested for prognostic value for disease-free survival (DFS) and overall survival (OS) using Cox regression models adjusted for treatment assignment, nodal status, and tumor size. RESULTS: Among 425 patients with TNBC, 33% were node positive. DDIR was tested successfully in 90% of patients (381 of 425), 62% of which were DDIR signature positive. DDIR signature positivity was associated with improved DFS (hazard ratio [HR], 0.67; 95% CI, 0.48 to 0.92; P = .015) and OS (HR, 0.61; 95% CI, 0.43 to 0.89; P = .010). sTILs density assessment was available in 99% of patients and was associated with improved DFS (HR, 0.70; 95% CI, 0.51 to 0.96; P = .026 for sTILs density ≥ 20% v < 20%) and OS (HR, 0.59; 95% CI, 0.41 to 0.85; P = .004 for sTILs density ≥ 20% v < 20%). DDIR signature score and sTILs density were moderately correlated (r = 0.60), which precluded statistical significance for DFS in a joint model. Three-year DFS and OS in a subgroup of patients with DDIR positivity and T1c/T2N0 disease were 88% and 94%, respectively. CONCLUSION: The prognostic role of sTILs and DDIR in early-stage TNBC was confirmed. DDIR signature conferred improved prognosis in two thirds of patients with TNBC treated with adjuvant AC. DDIR signature has the potential to stratify outcome and to identify patients with less projected benefit after AC chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/imunologia , Adulto , Idoso , Ciclofosfamida/uso terapêutico , Dano ao DNA , Intervalo Livre de Doença , Doxorrubicina/uso terapêutico , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Pessoa de Meia-Idade , Prognóstico , Transcriptoma , Neoplasias de Mama Triplo Negativas/mortalidade
17.
Clin Cancer Res ; 25(24): 7388-7395, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31515457

RESUMO

PURPOSE: Adjuvant therapy for small, node-negative HER2-positive breast cancer (HER2+ BC) is controversial. We aimed to identify the subgroup that would benefit most from adjuvant chemotherapy and trastuzumab. EXPERIMENTAL DESIGN: We reviewed records of patients with pT1N0M0 HER2+ BC treated at our institution from January 1, 1998, through October 31, 2009. We compared three groups: A, no adjuvant chemotherapy; B, adjuvant chemotherapy only; and C, adjuvant chemotherapy with trastuzumab. We evaluated disease-free survival (DFS), overall survival (OS), distant recurrence-free survival (DRFS), and breast cancer-specific survival (BCSS) in each group. RESULTS: We reviewed 587 consecutive patients with a median follow-up of 123.0 months. The 10-year DFS rate was 81.0%, 65.4%, and 97.3% in groups A, B, and C, respectively (P < 0.001). The restricted mean survival time ratio did not differ between groups A and B [ratio = 0.982; 95% confidence interval (CI), 0.930-1.036; P = 0.498). Cox regression showed that adjuvant chemotherapy with trastuzumab was associated with better DFS compared with no adjuvant chemotherapy [hazard ratio (HR), 0.071; 95% CI, 0.025-0.204; P < 0.001). Larger tumor size was associated with short DFS (HR, 2.384; 95% CI, 1.549-3.056; P < 0.001); improvements in DFS, OS, DRFS, and BCSS were observed with adjuvant chemotherapy plus trastuzumab in patients with tumors ≥0.8-cm diameter. Receiving adjuvant chemotherapy with trastuzumab was not associated with improved DFS, OS, or DRFS for tumors <0.8 cm. CONCLUSIONS: Adjuvant chemotherapy plus trastuzumab should be recommended for patients with pT1N0M0 HER2+ BC ≥0.8 cm in diameter; adjuvant therapy may not be necessary for tumors <0.8 cm.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/mortalidade , Quimioterapia Adjuvante/mortalidade , Linfonodos/patologia , Receptor ErbB-2/metabolismo , Sobreviventes/estatística & dados numéricos , Trastuzumab/uso terapêutico , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Humanos , Linfonodos/efeitos dos fármacos , Estadiamento de Neoplasias , Taxa de Sobrevida , Resultado do Tratamento
18.
Clin Cancer Res ; 25(20): 6089-6097, 2019 10 15.
Artigo em Inglês | MEDLINE | ID: mdl-31358544

RESUMO

PURPOSE: Metastasis requires malignant cell circulation from the primary to a distant tissue. Elevated levels of circulating tumor cells (CTC) portend a poor prognosis in breast and other cancers. Recent studies have suggested that CTC clusters may be a factor in the metastatic process. We conducted a prospective retrospective study of the SWOG0500 clinical trial to test whether CTC clusters are associated with poorer prognosis. EXPERIMENTAL DESIGN: CTC CellSearch galleries from SWOG0500 trial were reread using prespecified criteria for CTC clusters, doublets, and enumeration. Survival analysis methods include Kaplan-Meier plots and log-rank tests. RESULTS: Patients were classified into three prognostic subgroups based on baseline CTC/7.5 mL whole blood (WB): Arm A: <5CTC; Arm B/C: ≥5CTC and then B (<5CTC) and C (≥5CTC)/7.5 mL WB at first follow-up. At baseline, 19% of patients had CTC doublets or clusters, which were more likely in Arm B/C versus Arm A (38% vs. 1.4%; P < 0.0001). Furthermore, doublets or clusters were significantly more common in patients who were ultimately assigned to Arm C versus B (54% vs. 25%; P < 0.0001). In Arm C, doublets and clusters were associated with worse overall survival than only doublets, clusters, or no doublets nor clusters at baseline (P = 0.008) and first follow-up (P = 0.010). When compared with enumeration alone, doublets, clusters, or both were not prognostic in patients who had 5-19 or ≥20 CTC/7.5 mL WB. CONCLUSIONS: In patients with metastatic breast cancer starting first-line chemotherapy, mortality is independent of the presence of CTC clusters, but rather depends on the number of CTC/7.5 mL WB.


Assuntos
Neoplasias da Mama/mortalidade , Células Neoplásicas Circulantes , Antineoplásicos/uso terapêutico , Neoplasias da Mama/sangue , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Contagem de Células , Ensaios Clínicos Fase III como Assunto , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Estadiamento de Neoplasias , Prognóstico , Estudos Prospectivos , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Retrospectivos , Resultado do Tratamento
19.
Cancer Cell ; 36(2): 168-178.e4, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31327656

RESUMO

Reactivation of T cell immunity by PD-1/PD-L1 immune checkpoint blockade has been shown to be a promising cancer therapeutic strategy. However, PD-L1 immunohistochemical readout is inconsistent with patient response, which presents a clinical challenge to stratify patients. Because PD-L1 is heavily glycosylated, we developed a method to resolve this by removing the glycan moieties from cell surface antigens via enzymatic digestion, a process termed sample deglycosylation. Notably, deglycosylation significantly improves anti-PD-L1 antibody binding affinity and signal intensity, resulting in more accurate PD-L1 quantification and prediction of clinical outcome. This proposed method of PD-L1 antigen retrieval may provide a practical and timely approach to reduce false-negative patient stratification for guiding anti-PD-1/PD-L1 therapy.


Assuntos
Anticorpos/imunologia , Antígeno B7-H1/metabolismo , Imuno-Histoquímica , Neoplasias/metabolismo , Peptídeo-N4-(N-acetil-beta-glucosaminil) Asparagina Amidase/metabolismo , Processamento de Proteína Pós-Traducional , Manejo de Espécimes/métodos , Células A549 , Especificidade de Anticorpos , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Tomada de Decisão Clínica , Reações Falso-Negativas , Glicosilação , Humanos , Células Jurkat , Células MCF-7 , Neoplasias/tratamento farmacológico , Neoplasias/imunologia , Seleção de Pacientes , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Células THP-1
20.
Breast Cancer Res ; 21(1): 78, 2019 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-31277699

RESUMO

BACKGROUND: The PI3K/AKT pathway is activated through PIK3CA or AKT1 mutations and PTEN loss in breast cancer. We conducted a phase II trial with an allosteric AKT inhibitor MK-2206 in patients with advanced breast cancer who had tumors with PIK3CA/AKT1 mutations and/or PTEN loss/mutation. METHODS: The primary endpoint was objective response rate (ORR). Secondary endpoints were 6-month progression-free survival (6 m PFS), predictive and pharmacodynamic markers, safety, and tolerability. Patients had pre-treatment and on-treatment biopsies as well as collection of peripheral blood mononuclear cells (PBMC) and platelet-rich plasma (PRP). Next-generation sequencing, immunohistochemistry, and reverse phase protein arrays (RPPA) were performed. RESULTS: Twenty-seven patients received MK-2206. Eighteen patients were enrolled into the PIK3CA/AKT1 mutation arm (cohort A): 13 had PIK3CA mutations, four had AKT1 mutations, and one had a PIK3CA mutation as well as PTEN loss. ORR and 6 m PFS were both 5.6% (1/18), with one patient with HR+ breast cancer and a PIK3CA E542K mutation experiencing a partial response (on treatment for 36 weeks). Nine patients were enrolled on the PTEN loss/mutation arm (cohort B). ORR was 0% and 6 m PFS was 11% (1/9), observed in a patient with triple-negative breast cancer and PTEN loss. The study was stopped early due to futility. The most common adverse events were fatigue (48%) and rash (44%). On pre-treatment biopsy, PIK3CA and AKT1 mutation status was concordant with archival tissue testing. However, two patients with PTEN loss based on archival testing had PTEN expression on the pre-treatment biopsy. MK-2206 treatment was associated with a significant decline in pAKT S473 and pAKT T308 and PI3K activation score in PBMC and PRPs, but not in tumor biopsies. By IHC, there was no significant decrease in median pAKT S473 or Ki-67 staining, but a drop was observed in both responders. CONCLUSIONS: MK-2206 monotherapy had limited clinical activity in advanced breast cancer patients selected for PIK3CA/AKT1 or PTEN mutations or PTEN loss. This may, in part, be due to inadequate target inhibition at tolerable doses in heavily pre-treated patients with pathway activation, as well as tumor heterogeneity and evolution in markers such as PTEN conferring challenges in patient selection. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01277757 . Registered 13 January 2011.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Classe I de Fosfatidilinositol 3-Quinases/genética , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-akt/genética , Adulto , Idoso , Biomarcadores , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Monitoramento de Medicamentos , Feminino , Compostos Heterocíclicos com 3 Anéis/farmacologia , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Inibidores de Proteínas Quinases/farmacologia , Resultado do Tratamento
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