Tumor expression data from neoadjuvant trial of cisplatin monotherapy in triple negative breast cancer patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Silver DP
PROVIDER: S-ECPF-GEOD-18864 | biostudies-other | 2010 Apr
REPOSITORIES: biostudies-other
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Project description:Evidence suggests that BRCA1 mutation associated tumors have increased sensitivity to DNA damaging agents like cisplatin. Sporadic triple negative breast cancers (TNBC) have many phenotypic similarities to BRCA1 tumors and may have a similar sensitivity to cisplatin. We tested the efficacy of cisplatin monotherapy in 28 TNBC patients in a single arm neoadjuvant trial with outcome measured by pathologic treatment response quantified using the Miller-Payne scale. We used microarrays gene expression profiles to determine tumor subtype of each trial tumor sample and to test various expression signatures for association with pathologic response to cisplatin. Pretreatment tumor samples from the clinical trial (N=24 with adequate tissue) were used for RNA extraction, linear amplification, biotin labeling and hybridization to Affymetrix U133 plus 2.0 arrays. A reference set of 51 primary breast tumors representing all subtypes of breast cancer were processed in a similar manner to include linear amplification, and hybridized to Affymetrix arrays.
2009-11-04 | E-GEOD-18864 | biostudies-arrayexpress
Project description:Evidence suggests that BRCA1 mutation associated tumors have increased sensitivity to DNA damaging agents like cisplatin. Sporadic triple negative breast cancers (TNBC) have many phenotypic similarities to BRCA1 tumors and may have a similar sensitivity to cisplatin. We tested the efficacy of cisplatin monotherapy in 28 TNBC patients in a single arm neoadjuvant trial with outcome measured by pathologic treatment response quantified using the Miller-Payne scale. We used microarrays gene expression profiles to determine tumor subtype of each trial tumor sample and to test various expression signatures for association with pathologic response to cisplatin.
2009-11-04 | GSE18864 | GEO
Project description:PURPOSE Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response. PATIENTS AND METHODS Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m(2) every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers. Results Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03). CONCLUSION Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.
| S-EPMC2834466 | biostudies-literature
Project description:BackgroundIn this phase II clinical trial, we evaluated the efficacy of the nonanthracycline combination of carboplatin and nab-paclitaxel in early stage triple-negative breast cancer (TNBC).Patients and methodsPatients with newly diagnosed stage II-III TNBC (n =?69) were treated with neoadjuvant carboplatin (area under the curve 6) every 28?days for four cycles plus nab-paclitaxel (100 mg/m2 ) weekly for 16?weeks. Pathological complete response (pCR) and residual cancer burden (RCB) were analyzed with germline mutation status, tumor-infiltrating lymphocytes (TILs), TNBC molecular subtype, and GeparSixto immune signature (GSIS).ResultsSixty-seven patients were evaluable for safety and response. Fifty-three (79%) patients experienced grade 3/4 adverse events, including grade 3 anemia (43%), neutropenia (39%), leukopenia (15%), thrombocytopenia (12%), fatigue (7%), peripheral neuropathy (7%), neutropenia (16%), and leukopenia (1%). Twenty-four patients (35%) had at least one dose delay, and 50 patients (72%) required dose reduction. Sixty-three (94%) patients completed scheduled treatment. The responses were as follows: 32 of 67 patients (48%) had pCR (RCB 0), 10 of 67 (15%) had RCB I, 19 of 67 (28%) had RCB II, 5 of 67 (7%) had RCB III, and 1 of 67 (2%) progressed and had no surgery. Univariate analysis showed that immune-hot GSIS and DNA repair defect (DRD) were associated with higher pCR with odds ratios of 4.62 (p = .005) and 4.76 (p = .03), respectively, and with RCB 0/I versus RCB II/III with odds ratio 4.80 (p = .01). Immune-hot GSIS was highly correlated with DRD status (p = .03), TIL level (p < .001), and TNBC molecular subtype (p < .001). After adjusting for age, race, stage, and grade, GSIS remained associated with higher pCR and RCB class 0/I versus II/III with odds ratios 7.19 (95% confidence interval [CI], 2.01-25.68; p = .002) and 8.95 (95% CI, 2.09-38.23; p = .003), respectively.ConclusionThe combination of carboplatin and nab-paclitaxel for early stage high-risk TNBC showed manageable toxicity and encouraging antitumor activity. Immune-hot GSIS is associated with higher pCR rate and RCB class 0/1. This study provides an additional rationale for using nonanthracycline platinum-based therapy for future neoadjuvant trials in early stage TNBCs. Clinical trial identification number: NCT01525966 IMPLICATIONS FOR PRACTICE: Platinum is an important neoadjuvant chemotherapy agent for treatment of early stage triple-negative breast cancer (TNBC). In this study, carboplatin and nab-paclitaxel were well tolerated and highly effective in TNBC, resulting in pathological complete response of 48%. In univariate and multivariate analyses adjusting for age, race, tumor stage and grade, "immune-hot" GeparSixto immune signature (GSIS) and DNA repair defect (DRD) were associated with higher pathological complete response (pCR) and residual cancer burden class 0/1. The association of immune-hot GSIS with higher pCR holds promise for de-escalating neoadjuvant chemotherapy for patients with early stage TNBC. Although GSIS is not routinely used in clinic, further development of this immune signature into a clinically applicable assay is indicated.
| S-EPMC7930424 | biostudies-literature
Project description:Systemic therapy for metastatic triple-negative breast cancer (TNBC) still remains challenging because there are no targeted agents or endocrine therapies currently available. The present case report documents the successful use of cisplatin monotherapy to manage a heavily pretreated TNBC patient showing poor response to therapy. The patient was a 51-year-old woman who had already undergone several lines of systemic chemotherapy for widespread TNBC. Although the mutation analysis performed on DNA isolated from blood cells and progressed lesion samples confirmed the tumor to be germline BRCA wild-type, cisplatin monotherapy was administered based on the increasing evidence of safety and efficacy of platinum for breast cancer. After three cycles of cisplatin treatment, the patient's metastatic lesions dramatically improved without any major toxicity, and she completed 17 cycles with good response. This case study indicates that patients with heavily pretreated TNBC can potentially achieve a good response to cisplatin monotherapy.
| S-EPMC7384912 | biostudies-literature
Project description:Gene expression data from 21 triple negative breast cancer samples treated with cisplatin & bevacizumab in the neoadjuvant setting as part of a clinical trial. Gene expression data RMA normalized was used to find predictors of platinum sensitivity
2018-02-19 | GSE103668 | GEO
Project description:The optimal neoadjuvant chemotherapy (NACT) regimen in triple-negative breast cancer (TNBC) has not been clearly defined. Achieving a pathologic complete response (pCR) provides important prognostic information, and, especially in TNBC, is considered a surrogate endpoint for event-free survival. Thus, many neoadjuvant studies in TNBC focus on this as a primary endpoint, and such information may be used for accelerated US Food and Drug Administration approval. Current controversies in the field include: (1) the role of platinum-based compounds; (2) the optimal chemotherapy backbone; and (3) the benefits of additional therapy after surgery. Conflicting results of 2 major studies adding carboplatin to NACT have highlighted the need to balance potential benefits to disease outcomes against increased toxicity. While the PROGECT study suggests efficacy of a nonanthracycline-containing regimen, this is observational data, and evidence in the form of a clinical trial remains to be seen. Data surrounding optimal taxane use support the use of nab-paclitaxel in place of paclitaxel in limited clinical situations. Although bevacizumab may increase pCR rates, this has not translated into survival benefit. Capecitabine shows promise in patients who have not achieved pCR after NACT. The neoadjuvant setting remains an important model for drug development. This review will focus on the most important and most current neoadjuvant trials in women with TNBC.
| S-EPMC5865448 | biostudies-literature
Project description:PurposeTo investigate the value of performing mid-treatment axillary ultrasound (AUS) in triple-negative breast cancer (TNBC) patients who are undergoing neoadjuvant systemic therapy (NAST) by determining the optimal cutoff number of abnormal nodes associated with residual nodal disease on surgical pathology.Materials and methodsThis sub-study, an interim analysis of an ongoing single-institution clinical trial enrolling patients with stage I-III TNBC, included 106 patients. Number of abnormal nodes at mid-treatment was assessed and recorded by experienced breast radiologists, who empirically categorized lymph nodes using a binary approach of sonographically-normal versus abnormal. Pathologic lymph node positivity was defined as presence of macrometastasis or micrometastasis in ≥1 axillary node from sentinel lymph node biopsy and/or axillary lymph node dissection.ResultsOf 106 patients, 26 (25 %) had residual nodal disease and 80 (75 %) had no nodal disease at surgery. Median number of abnormal nodes at mid-treatment was 5 (standard deviation [SD], 5) for patients with residual nodal disease and 0 (SD, 2) for patients with no nodal disease at surgery (p < 0.0001). TNBC patients with >4 abnormal nodes at mid-treatment had a significantly higher chance of being node-positive at surgery (AUC = 0.908, p < 0.0001; PPV = 90 %).ConclusionOur data suggest that a cutoff of >4 abnormal nodes on mid-treatment AUS is associated with residual disease post-NAST. If our findings are substantiated by subsequent analyses, then mid-treatment AUS could be used to identify patients unlikely to achieve nodal pathologic complete response and who should be offered alternative therapy.
| S-EPMC7534548 | biostudies-literature
Project description:PURPOSE:As triple-negative breast cancers are associated with earlier recurrences and poorer survival, optimal treatment of early-stage breast cancer is essential. Several retrospective studies in triple-negative breast cancer have reported conflicting results in overall survival in patients receiving neoadjuvant or adjuvant systemic therapy. This study aims to analyze outcomes of adjuvant versus neoadjuvant in patients with early-stage triple-negative breast cancer with and without BRCA germline mutations. METHODS:Patients with stage I or II triple-negative breast cancer who had BRCA testing were identified from a prospective cohort study of 4027 patients. Clinical, demographic, genetic test results, chemotherapy, recurrence, and survival data were analyzed. Overall survival and disease-free survival were estimated using the Kaplan-Meier method. RESULTS:319 patients with stage I and II triple-negative breast cancer who met eligibility criteria were included in the analysis. 187 received adjuvant chemotherapy (58.6%) and 132 received neoadjuvant chemotherapy (41.4%). 135 were BRCA positive (42.3%) and 184 were BRCA negative (57.7%). There was no significant association between overall survival or disease-free survival and treatment with neoadjuvant versus adjuvant in the overall cohort. Furthermore, there were no significant differences between patient subgroups (neoadjuvant BRCA positive, neoadjuvant BRCA negative, adjuvant BRCA positive, and adjuvant BRCA negative) with respect to either overall survival or disease-free survival. CONCLUSIONS:Neoadjuvant versus adjuvant with standard anthracycline- and taxane-containing regimens results in similar disease-free survival and overall survival among patients with stage I and II triple-negative breast cancer regardless of BRCA status. Further studies are needed to evaluate whether similar results are observed with newer agents.
| S-EPMC5994186 | biostudies-literature
Project description:BACKGROUND:The focus of this study is to identify particular microRNA (miRNA) signatures in exosomes derived from plasma of 435 human epidermal growth factor receptor 2 (HER2)-positive and triple-negative (TN) subtypes of breast cancer (BC). METHODS:First, miRNA expression profiles were determined in exosomes derived from the plasma of 15 TNBC patients before neoadjuvant therapy using a quantitative TaqMan real-time PCR-based microRNA array card containing 384 different miRNAs. Forty-five miRNAs associated with different clinical parameters were then selected and mounted on microRNA array cards that served for the quantification of exosomal miRNAs in 435 BC patients before therapy and 20 healthy women. Confocal microscopy, Western blot, and ELISA were used for exosome characterization. RESULTS:Quantification of 45 exosomal miRNAs showed that compared with healthy women, 10 miRNAs in the entire cohort of BC patients, 13 in the subgroup of 211 HER2-positive BC, and 17 in the subgroup of 224 TNBC were significantly deregulated. Plasma levels of 18 exosomal miRNAs differed between HER2-positive and TNBC subtypes, and 9 miRNAs of them also differed from healthy women. Exosomal miRNAs were significantly associated with the clinicopathological and risk factors. In uni- and multivariate models, miR-155 (p?=?0.002, p?=?0.003, respectively) and miR-301 (p?=?0.002, p?=?0.001, respectively) best predicted pathological complete response (pCR). CONCLUSION:Our findings show a network of deregulated exosomal miRNAs with specific expression patterns in exosomes of HER2-positive and TNBC patients that are also associated with clinicopathological parameters and pCR within each BC subtype.
| S-EPMC6178264 | biostudies-other