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1.
J Mol Diagn ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31669227

RESUMO

Mutations in the ligand-binding domain (LBD) of the ESR1 gene result in resistance to estrogen deprivation therapy (EDT) in breast cancer. Their detection might enable optimization of therapy strategies. However, the predictive utility of the primary tumor (PT) is limited and obtaining serial biopsies of metastatic lesions is challenging. To underline their application as a liquid biopsy, single circulating tumor cells (CTCs) were analyzed with a next generation sequencing approach for the ESR1 coding region. CTCs from 46 metastatic luminal breast cancer patients were enriched using CellSearch system and isolated by micromanipulation. Their genomic DNA was amplified and the ESR1 gene was sequenced. Furthermore, tissue samples from corresponding PTs and/or metastatic lesions were investigated. ESR1 mutations were detected in 12 patients-exclusively in patients treated with EDT (P-value: 0.048). In seven cases mutations were located in the hotspot regions in the LBD. Six novel mutations were identified. ESR1 mutations were absent in PT tissue samples and were detected only in metastases obtained after CTC characterization. Single cell CTC analysis for ESR1 mutations could be of clinical value to identify patients who progress under EDT and therefore benefit from an early switch to an alternative ET or other treatment regimens. These data indicate that mutations outside the LBD's hotspot regions might also contribute to resistance to EDT.

2.
Fertil Steril ; 112(4): 731-739.e1, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31371054

RESUMO

OBJECTIVE: To study how genetics may play a role in determining risk of chemotherapy-related amenorrhea (CRA) in young women with breast cancer. DESIGN: Genome-wide association study. SETTING: Not applicable. PATIENT(S): Premenopausal women ≤45 years of age enrolled in one of these three trials were included if they had at least one menstrual case report form after chemotherapy ended and if they were of European ancestry. Forms during and up to 3 months after receipt of GnRH agonist were excluded. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The association of single-nucleotide polymorphisms with post-chemotherapy menstruation adjusted for trial and arm, age, tamoxifen use, and nodal status. RESULT(S): The median age of the 1,168 women was 41 years (range 19-45). Among these, 457 (39%) never resumed menses after chemotherapy. Older age, tamoxifen use, and node-negative disease were associated with increased risk of CRA. Adjusting for these, rs147451859, in an intron of PPCDC (phosphopantothenoylcysteine decarboxylase), and rs17587029, located 5' upstream of RPS20P11 (ribosomal protein S20 pseudogene 11), were associated with post-chemotherapy menstruation. CONCLUSION(S): Genetic variation may contribute to risk of CRA. Better prediction of who will experience CRA may inform reproductive and treatment decision making in young women with cancer.

3.
Sci Rep ; 9(1): 12524, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31467304

RESUMO

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

4.
Physiol Behav ; 209: 112584, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31228497

RESUMO

The aim of the present work is to investigate the association of salivary and cumulative cortisol levels with emotional and behavioral symptoms in a Franconian Cognition and Emotion Studies (FRANCES) general population cohort of 158 6- to 9 year old children. Salivary cortisol values were measured by one-day diurnal cortisol profile, whereas cumulative cortisol was estimated via one-month hair cortisol concentrations (rHCC). Nearly all significant associations of clinical symptoms with child cortisol indices were age dependent: We report emotional symptoms being associated with lower rHCC in younger children (6.06-7.54 years). In older children (7.55-9.41 years) behavioral problems were further associated with higher rHCC and lower salivary cortisol awakening responses. In summary, child clinical symptoms were stronger associated with markers of hair cortisol compared to salivary cortisol. To picture developmental mechanisms, we suggest longitudinal designs for cortisol measures of stress systems in children and adolescents.

5.
Int J Epidemiol ; 48(3): 781-794, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31243447

RESUMO

BACKGROUND: Evidence linking breast size to breast cancer risk has been inconsistent, and its interpretation is often hampered by confounding factors such as body mass index (BMI). Here, we used linkage disequilibrium score regression and two-sample Mendelian randomization (MR) to examine the genetic associations between BMI, breast size and breast cancer risk. METHODS: Summary-level genotype data from 23andMe, Inc (breast size, n = 33 790), the Breast Cancer Association Consortium (breast cancer risk, n = 228 951) and the Genetic Investigation of ANthropometric Traits (BMI, n = 183 507) were used for our analyses. In assessing causal relationships, four complementary MR techniques [inverse variance weighted (IVW), weighted median, weighted mode and MR-Egger regression] were used to test the robustness of the results. RESULTS: The genetic correlation (rg) estimated between BMI and breast size was high (rg = 0.50, P = 3.89x10-43). All MR methods provided consistent evidence that higher genetically predicted BMI was associated with larger breast size [odds ratio (ORIVW): 2.06 (1.80-2.35), P = 1.38x10-26] and lower overall breast cancer risk [ORIVW: 0.81 (0.74-0.89), P = 9.44x10-6]. No evidence of a relationship between genetically predicted breast size and breast cancer risk was found except when using the weighted median and weighted mode methods, and only with oestrogen receptor (ER)-negative risk. There was no evidence of reverse causality in any of the analyses conducted (P > 0.050). CONCLUSION: Our findings indicate a potential positive causal association between BMI and breast size and a potential negative causal association between BMI and breast cancer risk. We found no clear evidence for a direct relationship between breast size and breast cancer risk.

6.
J Clin Oncol ; 37(25): 2206-2216, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31157583

RESUMO

PURPOSE: The KRISTINE study compared neoadjuvant trastuzumab emtansine plus pertuzumab (T-DM1+P) with docetaxel, carboplatin, trastuzumab plus P (TCH+P) for the treatment human epidermal growth factor receptor 2-positive stage II to III breast cancer. T-DM1+P led to a lower pathologic complete response rate (44.4% v 55.7%; P = .016), but fewer grade 3 or greater and serious adverse events (AEs). Here, we present 3-year outcomes from KRISTINE. METHODS: Patients were randomly assigned to neoadjuvant T-DM1+P or TCH+P every 3 weeks for six cycles. Patients who received T-DM1+P continued adjuvant T-DM1+P, and patients who received TCH+P received adjuvant trastuzumab plus pertuzumab. Secondary end points included event-free survival (EFS), overall survival, patient-reported outcomes (measured from random assignment), and invasive disease-free survival (IDFS; measured from surgery). RESULTS: Of patients, 444 were randomly assigned (T-DM1+P, n = 223; TCH+P, n = 221). Median follow-up was 37 months. Risk of an EFS event was higher with TDM-1+P (hazard ratio [HR], 2.61 [95% CI, 1.36 to 4.98]) with more locoregional progression events before surgery (15 [6.7%] v 0). Risk of an IDFS event after surgery was similar between arms (HR, 1.11 [95% CI, 0.52 to 2.40]). Pathologic complete response was associated with a reduced risk of an IDFS event (HR, 0.24 [95% CI, 0.09 to 0.60]) regardless of treatment arm. Overall, grade 3 or greater AEs (31.8% v 67.7%) were less common with T-DM1+P. During adjuvant treatment, grade 3 or greater AEs (24.5% v 9.9%) and AEs leading to treatment discontinuation (18.4% v 3.8%) were more common with T-DM1+P. Patient-reported outcomes favored T-DM1+P during neoadjuvant treatment and were similar to trastuzumab plus pertuzumab during adjuvant treatment. CONCLUSION: Compared with TCH+P, T-DM1+P resulted in a higher risk of an EFS event owing to locoregional progression events before surgery, a similar risk of an IDFS event, fewer grade 3 or greater AEs during neoadjuvant treatment, and more AEs leading to treatment discontinuation during adjuvant treatment.

7.
Breast Cancer ; 26(6): 826-834, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31254201

RESUMO

BACKGROUND: Information on deaths occurring during oncological clinical trials has never been systematically assessed. Here, we examine the incidence of death and the profile of patients who died during randomized clinical breast cancer (BC) trials. METHODS: Information on fatal events during German Breast Group (GBG) led BC trials was prospectively captured. Data were derived from the trial databases and death narratives. All deaths were evaluated for possible causes, underlying conditions, treatment relatedness, time point and rate of autopsies. RESULTS: From 12/1996 to 01/2017, 23,387 patients were treated within 32 trials. Of those 88 (0.4%) died on therapy within 17 trials. Median age was 64 [range 35-84] years, 63.2% of patients had a body mass index (BMI) ≥ 25 kg/m2; 65.9% 1-3 and 22.7% ≥ 4 comorbidities; 61.4% 1-2 cardiovascular risk factors (CRFs); 26.4% took > 3 drugs; 81.7% had ECOG 0; 50.0% stage III, 76.7% luminal BC. The main causes of death were infection (38.6%; of those, 82.3% sepsis, 17.6% pneumonia), heart failure (14.8%), and pulmonary embolism (13.6%). Fatal events mainly occurred within the first 4 therapy cycles (55.7%), in the investigational arm (66.7%) and under anthracycline-taxane-based chemotherapy (51.1%). A relationship with the treatment was declared in 27.3% of the cases. An autopsy was performed in 13.6% of patients. CONCLUSIONS: Death during study treatment was mainly related to infections, and patients with advanced disease, high BMI, underlying comorbidities, CRFs and concomitant medications. If considered for study participation these patients need careful monitoring due to their higher risk for death on study.

9.
Breast Cancer Res ; 21(1): 60, 2019 05 10.
Artigo em Inglês | MEDLINE | ID: mdl-31077239

RESUMO

BACKGROUND: The incidence of central nervous system (CNS) metastases in breast cancer patients is rising and has become a major clinical challenge. Only few data are published concerning risk factors for the development of CNS metastases as a first site of metastatic disease in breast cancer patients. Moreover, the incidence of CNS metastases after modern neoadjuvant treatment is not clear. METHODS: We analyzed clinical factors associated with the occurrence of CNS metastases as the first site of metastatic disease in breast cancer patients after neoadjuvant treatment in the trials GeparQuinto and GeparSixto (n = 3160) where patients received targeted treatment in addition to taxane and anthracycline-based chemotherapy. RESULTS: After a median follow-up of 61 months, 108 (3%) of a total of 3160 patients developed CNS metastases as the first site of recurrence and 411 (13%) patients had metastatic disease outside the CNS. Thirty-six patients (1%) developed both CNS metastases and other distant metastases as the first site of metastatic disease. Regarding subtypes of the primary tumor, 1% of luminal A-like (11/954), 2% of luminal B-like (7/381), 4% of HER2-positive (34/809), and 6% of triple-negative patients (56/1008) developed CNS metastases as the first site of metastatic disease. In multivariate analysis, risk factors for the development of CNS metastases were larger tumor size (cT3-4; HR 1.63, 95% CI 1.08-2.46, p = 0.021), node-positive disease (HR 2.57, 95% CI 1.64-4.04, p < 0.001), no pCR after neoadjuvant chemotherapy (HR 2.29, 95% CI 1.32-3.97, p = 0.003), and HER2-positive (HR 3.80, 95% CI 1.89-7.64, p < 0.001) or triple-negative subtype (HR 6.38, 95% CI 3.28-12.44, p < 0.001). CONCLUSIONS: Especially patients with HER2-positive and triple-negative tumors are at risk of developing CNS metastases despite effective systemic treatment. A better understanding of the underlying mechanisms is required in order to develop potential preventive strategies.

10.
Breast Cancer Res ; 21(1): 68, 2019 05 22.
Artigo em Inglês | MEDLINE | ID: mdl-31118087

RESUMO

BACKGROUND: Mammographic breast density, adjusted for age and body mass index, and a polygenic risk score (PRS), comprised of common genetic variation, are both strong risk factors for breast cancer and increase discrimination of risk models. Understanding their joint contribution will be important to more accurately predict risk. METHODS: Using 3628 breast cancer cases and 5126 controls of European ancestry from eight case-control studies, we evaluated joint associations of a 77-single nucleotide polymorphism (SNP) PRS and quantitative mammographic density measures with breast cancer. Mammographic percent density and absolute dense area were evaluated using thresholding software and examined as residuals after adjusting for age, 1/BMI, and study. PRS and adjusted density phenotypes were modeled both continuously (per 1 standard deviation, SD) and categorically. We fit logistic regression models and tested the null hypothesis of multiplicative joint associations for PRS and adjusted density measures using likelihood ratio and global and tail-based goodness of fit tests within the subset of six cohort or population-based studies. RESULTS: Adjusted percent density (odds ratio (OR) = 1.45 per SD, 95% CI 1.38-1.52), adjusted absolute dense area (OR = 1.34 per SD, 95% CI 1.28-1.41), and the 77-SNP PRS (OR = 1.52 per SD, 95% CI 1.45-1.59) were associated with breast cancer risk. There was no evidence of interaction of the PRS with adjusted percent density or dense area on risk of breast cancer by either the likelihood ratio (P > 0.21) or goodness of fit tests (P > 0.09), whether assessed continuously or categorically. The joint association (OR) was 2.60 in the highest categories of adjusted PD and PRS and 0.34 in the lowest categories, relative to women in the second density quartile and middle PRS quintile. CONCLUSIONS: The combined associations of the 77-SNP PRS and adjusted density measures are generally well described by multiplicative models, and both risk factors provide independent information on breast cancer risk.

11.
J Clin Oncol ; 37(25): 2226-2234, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31082269

RESUMO

PURPOSE: The GeparSepto trial demonstrated that weekly nanoparticle albumin-bound (NAB)-paclitaxel significantly improves the pathologic complete remission rate compared with weekly solvent-based (sb) paclitaxel followed by epirubicin plus cyclophosphamide as neoadjuvant treatment in patients with primary breast cancer (BC). Here, we report data on long-term outcomes. METHODS: Patients with histologically confirmed primary BC were randomly assigned in a 1:1 ratio to 12 times weekly NAB-paclitaxel 150 mg/m2 (after study amendment, 125 mg/m2) or weekly sb-paclitaxel 80 mg/m2 followed in both arms by four times epirubicin 90 mg/m2 plus cyclophosphamide 600 mg/m2 every 3 weeks. Patients with human epidermal growth factor receptor 2 (HER2)-positive BC received dual antibody treatment with trastuzumab (8 mg/kg loading dose followed by 6 mg/kg every 3 weeks) and pertuzumab (840 mg loading dose followed by 420 mg every 3 weeks) concurrently to chemotherapy and continued for 1 year. RESULTS: A total of 1,206 patients started treatment, 606 with NAB-paclitaxel and 600 with sb-paclitaxel. After a median follow-up of 49.6 months (range, 0.5 to 64.0 months), 243 invasive disease-free survival (iDFS) events were reported (143 in the sb-paclitaxel and 100 in the NAB-paclitaxel arm). At 4 years, overall patients treated with NAB-paclitaxel had a significantly better iDFS compared with sb-paclitaxel (84.0% v 76.3%; hazard ratio, 0.66; 95% CI, 0.51 to 0.86; P = .002), whereas overall survival did not significantly differ between the two treatment arms (89.7% v 87.2%, respectively; hazard ratio, 0.82; 95% CI, 0.59 to 1.16; P = .260). Long-term follow-up of the treatment-related peripheral sensory neuropathy (PSN) showed a significant decrease of the median time to resolve PSN after NAB-paclitaxel 125 mg/m2 compared with NAB-paclitaxel 150 mg/m2. CONCLUSION: The significantly higher pathologic complete response rate with NAB-paclitaxel translated into a significantly improved iDFS in patients with early BC as compared with sb-paclitaxel. PSN improved much faster under NAB-paclitaxel 125 mg/m2 compared with NAB-paclitaxel 150 mg/m2.

12.
Breast Cancer Res Treat ; 176(3): 557-568, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31065870

RESUMO

PURPOSE: Ki-67 has been clinically validated for risk assessment in breast cancer, but the analytical validation and cutpoint-definition remain a challenge. Intraclass correlation coefficients (ICCs) are a statistical parameter for Ki-67 interobserver performance. However, the maximum degree of variance among pathologists allowed for meaningful biomarker results has not been defined. METHODS: Different amounts of variance were added to central pathology Ki-67 data (n = 9069) from three cohorts (IBCSGVIII + IX, BIG1-98, GeparTrio) by simulation of 4500 evaluations for each cohort, which were grouped by ICCs, ranging from excellent (ICC = 0.9) to poor concordance (ICC = 0.1). Endpoints were disease-free survival (DFS) and pathological complete response (pCR, GeparTrio). RESULTS: Ki-67 was a significant continuous prognostic marker for DFS over a wide range of cutpoints between 8% and 30% in all three cohorts. In our modelling approach, Ki-67 was a stable prognostic marker despite increased interpathologist variance. Even for a poor ICC of 0.5, one or more significant Ki-67 cutoffs were detected in 86.8% (GeparTrio), 92.4% (IBCSGVIII + IX) and 100% of analyses (BIG1-98). Similarly, in GeparTrio, even with an extremely low ICC of 0.2, 99.6% of analyses were significant for pCR. CONCLUSIONS: Our study shows that Ki-67 is a continuous marker which is extremely robust to pathologist variation. Even if only 50% of variance is attributable to true Ki-67-based proliferation (ICC = 0.5), this information is sufficient to obtain statistically significant differences in clinical cohorts. This stable performance explains the observation that many Ki-67 studies achieve significant results despite relevant interobserver variance and points to a high clinical validity of this biomarker. For clinical decisions based on analysis of individual patient data, ongoing efforts to further reduce interobserver variability, including ring trials and standardized guidelines as well as image analysis approaches, should be continued.

13.
Clin Cancer Res ; 25(13): 3986-3995, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30979740

RESUMO

PURPOSE: Next-generation sequencing (NGS) can be used for comprehensive investigation of molecular events in breast cancer. We evaluated the relevance of genomic alterations for response to neoadjuvant chemotherapy (NACT) in the GeparSepto trial. EXPERIMENTAL DESIGN: Eight hundred fifty-one pretherapeutic formalin-fixed paraffin-embedded (FFPE) core biopsies from GeparSepto study were sequenced. The panel included 16 genes for mutational (AKT1, BRAF, CDH1, EGFR, ERBB2, ESR1, FBXW7, FGFR2, HRAS, KRAS, NRAS, SF3B1, TP53, HNF1A, PIK3CA, and PTEN) and 8 genes for copy-number alteration analysis (CCND1, ERBB2, FGFR1, PAK1, PIK3CA, TOP2A, TP53, and ZNF703). RESULTS: The most common genomic alterations were mutations of TP53 (38.4%) and PIK3CA (21.5%), and 8 different amplifications (TOP2A 34.9%; ERBB2 30.6%; ZNF703 30.1%; TP53 21.9%; PIK3CA 24.1%; CCND1 17.7%; PAK1 14.9%; FGFR 12.6%). All other alterations had a prevalence of less than 5%. The genetic heterogeneity in different breast cancer subtypes [lum/HER2neg vs. HER2pos vs. triple-negative breast cancer (TNBC)] was significantly linked to differences in NACT response. A significantly reduced pathologic complete response rate was observed in PIK3CA-mutated breast cancer [PIK3CAmut: 23.0% vs. wild-type (wt) 38.8%, P < 0.0001] in particular in the HER2pos subcohort [multivariate OR = 0.43 (95% CI, 0.24-0.79), P = 0.006]. An increased response to nab-paclitaxel was observed only in PIK3CAwt breast cancer, with univariate significance for the complete cohort (P = 0.009) and the TNBC (P = 0.013) and multivariate significance in the HER2pos subcohort (test for interaction P = 0.0074). CONCLUSIONS: High genetic heterogeneity was observed in different breast cancer subtypes. Our study shows that FFPE-based NGS can be used to identify markers of therapy resistance in clinical study cohorts. PIK3CA mutations could be a major mediator of therapy resistance in breast cancer.

14.
Int J Cancer ; 145(8): 2114-2121, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30901076

RESUMO

One of the most common adverse events (AEs) occurring during treatment with aromatase inhibitors (AIs) is musculoskeletal pain. The aim of our study was to analyze the influence of preexisting muscle/limb pain and joint pain on the development of AI-induced musculoskeletal AEs. Women eligible for upfront adjuvant endocrine therapy with letrozole were included in the PreFace study, a multicenter phase IV trial. During the first treatment year, they were asked to record musculoskeletal AEs monthly by answering questions regarding pain symptoms and rating the pain intensity on a numeric rating scale from 0 (no pain) to 10 (very strong pain). Pain values were compared using nonparametric statistical tests. Overall, 1,416 patients were evaluable. The average pain value over all time points in women with preexisting muscle/limb pain was 4.3 (median 4.3); in those without preexisting pain, it was 2.0 (median 1.7). In patients without preexisting muscle/limb pain, pain levels increased relatively strongly within the first 6 months (mean increase +0.9, p < 0.00001) in comparison with those with preexisting pain (mean increase +0.3, p < 0.001), resulting in a statistically significant difference (p < 0.00001) between the two groups. The development of joint pain was similar in the two groups. Women without preexisting muscle/limb pain or joint pain have the greatest increase in pain after the start of adjuvant AI therapy. Women with preexisting pain have significantly higher pain values. The main increase in pain values takes place during the first 6 months of treatment.

15.
Breast Cancer Res Treat ; 175(3): 617-625, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30868391

RESUMO

PURPOSE: Several clinical trials have investigated the prognostic and predictive usefulness of molecular markers. With limited predictive value, molecular markers have mainly been used to identify prognostic subgroups in which the indication for chemotherapy is doubtful and the prognosis is favorable enough for chemotherapy to be avoided. However, limited information is available about which groups of patients may benefit from additional therapy. This study aimed to describe the prognostic effects of Ki-67 in several common subgroups of patients with early breast cancer. METHODS: This retrospective study analyzed a single-center cohort of 3140 patients with HER2-, hormone receptor-positive breast cancer. Five-year disease-free survival (DFS) rates were calculated for low (< 10%), intermediate (10-19%), and high (≥ 20%) Ki-67 expression levels, as assessed by immunohistochemistry, and for subgroups relative to age, body mass index, disease stage, tumor grade, and (neo-)adjuvant chemotherapy. It was also investigated whether Ki-67 had different effects on DFS in these subgroups. RESULTS: The 5-year DFS rates for patients with low, intermediate, and high levels of Ki-67 expression were 0.90, 0.89, and 0.77, respectively. Ki-67 was able to further differentiate patients with an intermediate prognosis into different prognostic groups relative to common clinical parameters. Patients with stage II breast cancer had 5-year DFS rates of 0.84, 0.88, and 0.79 for low, intermediate, and high levels of Ki-67 expression. Ki-67 had different prognostic effects in subgroups defined by age and tumor grade. CONCLUSIONS: Ki-67 may help identify patients in intermediate prognostic groups with an unfavorable prognosis who may benefit from further therapy.

16.
Clin Cancer Res ; 25(10): 2975-2987, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-30723140

RESUMO

PURPOSE: Addition of alpelisib to fulvestrant significantly extended progression-free survival in PIK3CA-mutant, hormone receptor-positive (HR+) advanced/metastatic breast cancer in the phase III SOLAR-1 study. The combination of alpelisib and letrozole also had promising activity in phase I studies of HR+ advanced/metastatic breast cancer. NEO-ORB aimed to determine whether addition of alpelisib to letrozole could increase response rates in the neoadjuvant setting.Patients and Methods: Postmenopausal women with HR+, human epidermal growth factor receptor 2-negative, T1c-T3 breast cancer were assigned to the PIK3CA-wild-type or PIK3CA-mutant cohort according to their tumor PIK3CA status, and randomized (1:1) to 2.5 mg/day letrozole with 300 mg/day alpelisib or placebo for 24 weeks. Primary endpoints were objective response rate (ORR) and pathologic complete response (pCR) rate for both PIK3CA cohorts. RESULTS: In total, 257 patients were assigned to letrozole plus alpelisib (131 patients) or placebo (126 patients). Grade ≥3 adverse events (≥5% of patients) in the alpelisib arm were hyperglycemia (27%), rash (12%), and maculo-papular rash (8%). The primary objective was not met; ORR in the alpelisib versus placebo arm was 43% versus 45% and 63% versus 61% in the PIK3CA-mutant and wild-type cohorts, respectively. pCR rates were low in all groups. Decreases in Ki-67 were similar across treatment arms and cohorts. In PIK3CA-mutant tumors, alpelisib plus letrozole treatment induced a greater decrease in phosphorylated AKT versus placebo plus letrozole. CONCLUSIONS: In contrast to initial results in advanced/metastatic disease, addition of alpelisib to 24-week neoadjuvant letrozole treatment did not improve response in patients with HR+ early breast cancer.

17.
Sci Rep ; 9(1): 2318, 2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30783124

RESUMO

In breast cancer (BC), elevated levels of urokinase-type plasminogen activator (uPA) in tumor tissue have been confirmed as a strong prognostic factor in level-of-evidence-1 studies. The aim of the present study was to evaluate the clinical relevance of uPA levels in serum of metastatic BC patients and to compare uPA with other blood-based biomarkers. 252 patients were enrolled in this prospective, multicentre study. Blood samples were collected before begin of first-line or later-line systemic treatment. Serum uPA was quantified by a commercially available ELISA. Circulating tumor cells (CTCs) were detected using CellSearch; other biomarkers (EGFR, VEGF, HER2, RAS p21, TIMP1, CAIX) by ELISA. Using the ROC analysis, the optimal cut-off value (determined by the Youden index) of serum uPA was 2.52 ng/ml. Using this value, 26% of patients had elevated uPA levels. Patients with visceral metastasis and more than one metastatic site were significantly more likely to present with elevated uPA levels. CTC status, serum HER2, RAS p21, CAIX, TIMP1 and VEGF correlated significantly with uPA levels. Elevated uPA levels predicted shorter overall and progression-free survival in univariate analysis (median OS: 7.5 months [95%-CI 4.5-10.5 months] vs. not reached, p < 0.001; PFS: 4.8 [95%-CI: 3.1-6.5] vs. 9.1 [7.4-10.8] months, p < 0.001). In multivariate analysis, elevated uPA, presence of ≥5 CTCs, elevated RAS p21, higher grading and higher line of therapy were independent predictors of shorter OS, while elevated CTC counts, higher line of therapy and negative estrogen receptor status were independent predictors of shorter PFS. In conclusion, elevated uPA levels independently predict reduced overall survival and improved prognostication in patients with known CTC status. Whether high serum uPA might identify patients most likely to benefit from therapies targeting uPA, remains to be evaluated in future trials.

18.
J Med Internet Res ; 21(1): e10004, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30668517

RESUMO

BACKGROUND: The most frequent malignant disease in women is breast cancer. In the metastatic setting, quality of life is the primary therapeutic goal, and systematic treatment has only a limited effect on survival rates; therefore, the concept of the health-related quality of life (HRQoL) and measurement of patient-reported outcomes (PROs) are gaining more and more importance in the therapy setting of diseases such as breast cancer. One of the frequently used questionnaires for measuring the HRQoL in patients with breast cancer is the Functional Assessment of Cancer Therapy-Breast (FACT-B). Currently, paper-based surveys still predominate, as only a few reliable and validated electronic-based questionnaires are available. ePRO tools for the FACT-B questionnaire with proven reliability are missing so far. OBJECTIVE: The aim of this study was to analyze the reliability of tablet-based measurement of FACT-B in the German language in adjuvant (curative) and metastatic breast cancer patients. METHODS: Paper- and tablet-based questionnaires were completed by a total of 106 female adjuvant and metastatic breast cancer patients. All patients were required to complete the electronically based (ePRO) and paper-based version of the FACT-B. A frequency analysis was performed to determine descriptive sociodemographic characteristics. Both dimensions of reliability (parallel forms reliability using Wilcoxon test and test of internal consistency using Spearman ρ) and agreement rates for single items, Kendall tau for each subscale, and total score were analyzed. RESULTS: High correlations were shown for both dimensions of reliability (parallel forms reliability and internal consistency) in the patients' response behavior between paper-based and electronically based questionnaires. Regarding the reliability test of parallel forms, no significant differences were found in 35 of 37 single items, while significant correlations in the test for consistency were found in all 37 single items, in all 5 sum individual item subscale scores, as well as in total FACT-B score. CONCLUSIONS: The ePRO version of the FACT-B questionnaire is reliable for patients with breast cancer in both adjuvant and metastatic settings, showing highly significant correlations with the paper-based version in almost all questions all subscales and the total score.

19.
Eur J Cancer Prev ; 28(6): 515-521, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30681416

RESUMO

Early breast cancer detection programs depend for effectiveness on the participation rate, which is affected by risk factor awareness. This study investigated changes in women's risk factor awareness between 2004 and 2016. Results from a 2004 survey of 2107 healthy women were compared with new data obtained using the same questionnaire in 2016, with 866 participants indicating their knowledge and perceptions regarding breast cancer incidence, risk factors, risk perceptions, and levels of concern. Logistic regression models assessed the influence of time point (2004 vs. 2016) on correct recognition of risk factors such as age at first childbirth, childlessness, lack of breastfeeding, hormone replacement therapy (HRT), and family history. Regression models were adjusted for common sociodemographic characteristics. Reproductive risk factors were regarded as influencing breast cancer risk less often. In 2004, age at first birth, childlessness, and lack of breastfeeding were regarded as risk factors by 24, 32, and 37%, respectively, in comparison with only 15, 18, and 23% in 2016. All changes were statistically significant. Awareness of HRT as a risk factor increased significantly (36-57%), and family history was recognized as a risk by 75 and 73% in 2004 and 2016, respectively. Most women recognized family history as a breast cancer risk factor. This did not change, reflecting the topic's media prominence. Awareness of HRT as a risk factor increased, probably owing to public information after the large HRT studies. It is unclear why reproductive risk factors are less frequently recognized; educational programs should address this information deficit.

20.
Breast ; 44: 81-89, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30690254

RESUMO

OBJECTIVES: In breast cancer, large tumor size, positive nodal stage and a triple-negative tumor subtype are associated with reduced survival, but the interactions between these prognostic factors are not well understood. MATERIAL AND METHODS: Here we re-evaluated the impact of tumor size, nodal stage and tumor subtype on disease-free survival (DFS), overall survival (OS), distant disease-free survival (DDFS) and breast cancer specific survival (BCSS) in a retrospective analysis using data from the adjuvant SUCCESS A trial. Subgroup analyses were conducted to assess whether the effect of tumor size and nodal stage on survival depended on tumor subtype. RESULTS: Increasing tumor size, higher nodal stage and triple negative breast cancer (TNBC) were associated with unfavorable prognosis (all p < 0.001). There was no significant interaction between tumor subtype and tumor size (p > 0.5 for all four survival endpoints), but we found significant interactions between tumor subtype and nodal stage (p < 0.05 for all four survival endpoints), with no differences in survival among tumor subtypes for patients with pN0 tumors (all p > 0.05) and pronounced differences in survival among tumor subtypes for patients with positive nodal stage (all p < 0.001). CONCLUSIONS: This analysis confirms tumor size, nodal stage and tumor subtype as independent prognostic factors in high-risk early breast cancer. Nodal-positive patients with TNBC had a considerably worse outcome compared to nodal-positive patients with another tumor subtype. This underlines the importance for early detection particularly for patients with TNBC. TRIAL REGISTRATION: EudraCT 2005-000490-21; ClinicalTrials.gov Identifier: NCT02181101.


Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Sobreviventes de Câncer/estatística & dados numéricos , Idoso , Biomarcadores Tumorais/análise , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias/estatística & dados numéricos , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia
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