scholarly journals Comprehensive Genomic Profile of Heterogeneous Long Follow-Up Triple-Negative Breast Cancer and Its Clinical Characteristics Shows DNA Repair Deficiency Has Better Prognostic

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1367
Author(s):  
Ernesto Rojas-Jiménez ◽  
Javier César Mejía-Gómez ◽  
Clara Díaz-Velásquez ◽  
Rosalía Quezada-Urban ◽  
Héctor Martínez Gregorio ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Dna Repair ◽  
Latin American ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Genomic Alterations ◽  
Driver Genes

Triple-negative breast cancer (TNBC) presents a marked diversity at the molecular level, which promotes a clinical heterogeneity that further complicates treatment. We performed a detailed whole exome sequencing profile of 29 Mexican patients with long follow-up TNBC to identify genomic alterations associated with overall survival (OS), disease-free survival (DFS), and pathologic complete response (PCR), with the aim to define their role as molecular predictive factors of treatment response and prognosis. We detected 31 driver genes with pathogenic mutations in TP53 (53%), BRCA1/2 (27%), CDKN1B (9%), PIK3CA (9%), and PTEN (9%), and 16 operative mutational signatures. Moreover, tumors with mutations in BRCA1/2 showed a trend of sensitivity to platinum salts. We found an association between deficiency in DNA repair and surveillance genes and DFS. Across all analyzed tumors we consistently found a heterogeneous molecular complexity in terms of allelic composition and operative mutational processes, which hampered the definition of molecular traits with clinical utility. This work contributes to the elucidation of the global molecular alterations of TNBC by providing accurate genomic data that may help forthcoming studies to improve treatment and survival. This is the first study that integrates genomic alterations with a long follow-up of clinical variables in a Latin American population that is an underrepresented ethnicity in most of the genomic studies.

scholarly journals BRCA1/2 Mutations and Bevacizumab in the Neoadjuvant Treatment of Breast Cancer: Response and Prognosis Results in Patients With Triple-Negative Breast Cancer From the GeparQuinto Study

2018 ◽  
Vol 36 (22) ◽  
pp. 2281-2287 ◽  
Author(s):  
Peter A. Fasching ◽  
Sibylle Loibl ◽  
Chunling Hu ◽  
Steven N. Hart ◽  
Hermela Shimelis ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Strong Predictor ◽  
Pathologic Complete Response ◽  
Neoadjuvant Treatment ◽  
Disease Free Survival ◽  
Hazard Ratio ◽  
Brca1 And Brca2 ◽  
Mutation Carriers

Purpose BRCA1/2 mutations are frequent in patients with triple-negative breast cancer (TNBC). These patients are often treated with primary systemic chemotherapy. The aim of this study was to analyze the effects of BRCA1/2 mutations on pathologic complete response (pCR) and disease-free survival (DFS) in a cohort of patients with TNBC treated with anthracycline and taxane–containing chemotherapy, with or without bevacizumab. Patients and Methods Germline DNA was sequenced to identify mutations in BRCA1 and BRCA2 in 493 patients with TNBC from the GeparQuinto study. The pCR rates were compared in patients with and without mutation, as well as in patients treated with and without bevacizumab. In addition, the influence of BRCA1/2 mutation status and pCR status on DFS was evaluated relative to treatment. Results BRCA1/2 mutations were detected in 18.3% of patients with TNBC. Overall, patients with mutations had a pCR rate of 50%, compared with 31.5% in patients without a mutation (odds ratio [OR], 2.17; 95% CI, 1.37 to 3.46; P = .001). The pCR rate among patients treated with bevacizumab was 61.5% for BRCA1/2 mutation carriers and 35.6% for those without mutations (OR, 2.90; 95% CI, 1.43 to 5.89; P = .004). pCR was a strong predictor of DFS for patients without BRCA1/2 mutations (hazard ratio, 0.18; 95% CI, 0.11 to 0.31) but not for patients with BRCA1/2 mutations (hazard ratio, 0.74; 95% CI, 0.32 to 1.69). Conclusion The addition of bevacizumab may increase the pCR after standard neoadjuvant chemotherapy for patients with TNBC with BRCA1/2 mutations. In patients treated with anthracycline and taxane–based chemotherapy (with or without bevacizumab), pCR was a weaker predictor of DFS for BRCA1/2 mutation carriers than for patients without mutations.

Docetaxel-carboplatin-bevacizumab (TCV): A novel combination that promises a high activity in triple-negative breast cancer: A pilot study.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11543-e11543
Author(s):  
Jose Ignacio Chacon ◽  
Ana Rosa Rubio Salvador(2) ◽  
Nazaret Cordero Franco(1) ◽  
Begona Martinez Carrasco (1) ◽  
Sonia Alonso Soler(1) ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Lymph Node Biopsy ◽  
Tolerability Profile ◽  
Good Tolerability ◽  
Highly Active

e11543 Background: Triple negative breast cancer (TNBC) is an anthracycline resistant subtype, for which there is no standard chemotherapy. Taxanes, platinum-derived drugs and bevacizumab all seem to be active drugs in this setting, but definitive data are still lacking. Our purpose is to report our experience with the combination Docetaxel-Carboplatin-Bevacizumab (TCV) in TNBC. Methods: We retrospectively analysed our database using medical claims for patients diagnosed with TNBC and treated with TCV in neoadjuvant (NAJ) or metastasic( MD), between July 1, 2009, and December 31, 2011. Informed consent was obtained from all patients. Results: 13 pts have received 86 TCV cycles, 8 in NAJ and 5 for MD. NAJ: Median age: 48(28-60) y. T3-T4 tumors: 62,5% . N+: 62.5%. All pts received 6 TCV cycles, except 1 pt, still on therapy. 5 (62.5%) pts received quadrantectomy, 2(25%) mastectomy as surgical treatment after TCV. One pt has not received surgery yet. Sentinel lymph node biopsy was done in 5/8 (62.5%) pts, the other 3 received axillary dissection for clinically N+ metastasis. After surgery, pathologic complete response (pCR) in breast in 6/7 pts (85.7%); in axillary nodes, pCR in 5/7 pts (71,4%). One has not been surgically evaluated yet. Median follow-up: 10 months (2-18). Only one pt has relapsed with cerebral metastasis. MD: Median age: 54.4 (40-71) y. 4 pts received TCV as first line, one as third line therapy. 3 pts obtained complete response, 2 partial responses, but both progressed in three months. Median follow-up: 14.4 months. Only one of these pts has died. Toxicity: Was mild, without any grade 3 or 4 toxic effect. Only one pt showed grade 2 hypertension after bevacizumab infusion. Neutropenia was not evaluable for use of G-CSF per protocol. Conclusions: Although this is a short series, it suggests that TCV may be a highly active combination in TNBC with a good tolerability profile. These data warrant continuing testing of this combination in TNBC.

A randomized, triple negative breast cancer enrolling trial to confirm molecular profiling improves survival (ARTEMIS).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS590-TPS590 ◽  
Author(s):  
Clinton Yam ◽  
Kenneth R. Hess ◽  
Jennifer Keating Litton ◽  
Wei Tse Yang ◽  
Helen Piwnica-Worms ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Triple Negative Breast Cancer ◽  
Primary Tumor ◽  
Triple Negative ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Disease Free Survival ◽  
Type I ◽  
Free Survival

TPS590 Background: Following neoadjuvant chemotherapy (NACT), patients (pts) with triple negative breast cancer (TNBC) achieving pathologic complete response/residual cancer burden-0 (pCR/RCB-0) or minimal residual disease (RCB-I) have an improved relapse free survival when compared to pts with more extensive residual disease (RCB-II/III) (Symmans et al, JCO 2017). Pts with chemo-resistant TNBC have a poor prognosis as there are currently no FDA-approved targeted agents available for TNBC. We previously reported the ability of a novel gene expression signature (GES) to predict sensitivity to NACT (Hatzis et al, JAMA 2011). Here we seek to prospectively validate the use of this GES in combination with imaging to predict response to NACT and establish the clinical impact of selecting pts predicted to have non-responsive disease (NRD) for enrollment in clinical trials of targeted therapy. Methods: All pts will undergo a biopsy of the primary tumor for molecular characterization (MC) and will be randomized 2:1 to know their MC results (intervention arm) or not (control arm). A maximum of 360 pts will be enrolled and randomized using a group sequential design with one-sided O’Brien-Fleming boundaries, with two equally spaced binding interim tests for futility and superiority and one final test, having an overall Type I error of 0.05 and power of 0.80 to detect an improvement in pCR/RCB-I from 50% to 64%. Secondary endpoints include rates of clinical trial enrollment, disease free survival and integrated biomarker analyses. All pts will receive 4 cycles of anthracycline-based NACT with imaging done every 2 cycles to assess response. After completion or progression on anthracycline-based NACT, pts predicted to have NRD based on MC/imaging (intervention arm) or imaging alone (control arm) will be offered enrollment on a clinical trial. Pts are eligible if they have stage I-III TNBC with a primary tumor that is ≥1.5cm. Pts with contraindications to anthracyclines and/or taxanes are excluded. Enrollment began in November 2015. 105 pts have been enrolled to date with 71 and 34 pts randomized to the intervention and control arms, respectively. Clinical trial information: NCT02276443.

Efficacy of epirubicin plus cyclophosphamide followed by taxanes versus carboplatin plus taxanes as adjuvant chemotherapy in triple-negative breast cancer: 8.1 years median follow-up on a randomized clinical trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 529-529
Author(s):  
Fangchao Zheng ◽  
Feng Du ◽  
Yongsheng Wang ◽  
Xue Wang ◽  
Jiayu Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Trial ◽  
Triple Negative Breast Cancer ◽  
Adjuvant Treatment ◽  
Subgroup Analysis ◽  
Triple Negative ◽  
Brca Mutation ◽  
Disease Free Survival ◽  
Open Label

529 Background: Four cycles of adjuvant taxanes (paclitaxel or docetaxel) after four cycles of adjuvant doxorubicin plus cyclophosphamide (ECT) are considered a standard adjuvant treatment and improves survival outcomes of triple negative breast cancer (TNBC). The purpose of this analysis was to further assess whether adjuvant carboplatin plus taxanes (TP) was non-inferior to or superior to standard ECT chemotherapy in prolonging the survival time. Methods: This randomized, open-label, multicenter clinical trial conducted at three hospital in China from June, 2009 and October, 2015. Eligible early triple-negative breast cancer (TNBC) patients were randomized (1:1) to receive ECT (four cycles of epirubicin 90 mg/m2 + cyclophosphamide 600 mg/m2 followed by four cycles of docetaxel 75 mg/m2 or paclitaxel 175 mg/m2 every 3 weeks, ECT arm, n = 154) or receive TP (six cycles of docetaxel 75 mg/m2 or paclitaxel 175 mg/m2 + carboplatin AUC 5 every 3 weeks; TP arm, n = 154), which was then followed by surgery. Results: Three hundred and eight patients were recruited in this trial and final date of follow-up was January 20, 2021. Baseline characteristics were balanced between ECT arm and TP arm. Median follow-up was 97.6 months. Median disease free survival (DFS) was not reached; 8-year DFS rate was 78.35% with ECT arm and 81.73% with TP arm (hazard ratio [HR] = 0.84; 95% confidence interval [CI] = 0.50 - 1.40; P = 0.496). Median overall survival (OS) was also not reached; 8-year OS rate was 87.15% with ECT arm and 89.14% with TP arm (HR = 0.87; 95% CI = 0.44 - 1.70; P = 0.676). For TNBC patients with DFS > 4 year, TP arm had a longer DFS than ECT ( P = 0.01), and had a tendency with better OS ( P = 0.4). In this subgroup analysis of SPARC > 50%, TP arm had a longer DFS than ECT ( P < 0.05), and also had a tendency with better OS ( P = 0.06). In subgroup analysis of PD-1 (-) and intravascular invasion (+), TP arm had a better DFS ( P = 0.02) and OS ( P = 0.03) than ECT arm. DFS or OS had no significant differences in ECT and TP arm with BRCA mutation or BRCA wild ( all P values > 0.05). Conclusions: TP chemotherapy showed significant non-inferiority for PFS and OS versus ECT in the first-line adjuvant treatment of early TNBC. For some particular subgroup of TNBC, TP may be a more effective chemotherapy than ECT. TP may be considered an effective alternative to early TNBC. Clinical trial information: NCT01150513.

scholarly journals An open-label, pilot study of veliparib and lapatinib in patients with metastatic, triple-negative breast cancer

2021 ◽  
Vol 23 (1) ◽  
Author(s):  
Erica M. Stringer-Reasor ◽  
Jori E. May ◽  
Eva Olariu ◽  
Valerie Caterinicchia ◽  
Yufeng Li ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gene Expression ◽  
Dna Repair ◽  
Pilot Study ◽  
Expression Analysis ◽  
Triple Negative Breast Cancer ◽  
Gene Expression Analysis ◽  
Triple Negative ◽  
Egfr Inhibition ◽  
Link Type

Abstract Background Poly (ADP-ribose)-polymerase inhibitors (PARPi) have been approved for cancer patients with germline BRCA1/2 (gBRCA1/2) mutations, and efforts to expand the utility of PARPi beyond BRCA1/2 are ongoing. In preclinical models of triple-negative breast cancer (TNBC) with intact DNA repair, we have previously shown an induced synthetic lethality with combined EGFR inhibition and PARPi. Here, we report the safety and clinical activity of lapatinib and veliparib in patients with metastatic TNBC. Methods A first-in-human, pilot study of lapatinib and veliparib was conducted in metastatic TNBC (NCT02158507). The primary endpoint was safety and tolerability. Secondary endpoints were objective response rates and pharmacokinetic evaluation. Gene expression analysis of pre-treatment tumor biopsies was performed. Key eligibility included TNBC patients with measurable disease and prior anthracycline-based and taxane chemotherapy. Patients with gBRCA1/2 mutations were excluded. Results Twenty patients were enrolled, of which 17 were evaluable for response. The median number of prior therapies in the metastatic setting was 1 (range 0–2). Fifty percent of patients were Caucasian, 45% African–American, and 5% Hispanic. Of evaluable patients, 4 demonstrated a partial response and 2 had stable disease. There were no dose-limiting toxicities. Most AEs were limited to grade 1 or 2 and no drug–drug interactions noted. Exploratory gene expression analysis suggested baseline DNA repair pathway score was lower and baseline immunogenicity was higher in the responders compared to non-responders. Conclusions Lapatinib plus veliparib therapy has a manageable safety profile and promising antitumor activity in advanced TNBC. Further investigation of dual therapy with EGFR inhibition and PARP inhibition is needed. Trial registration ClinicalTrials.gov, NCT02158507. Registered on 12 September 2014

scholarly journals Triple negative breast cancer subtypes and pathologic complete response rate to neoadjuvant chemotherapy

Oncotarget ◽  
2018 ◽  
Vol 9 (41) ◽  
pp. 26406-26416 ◽  
Author(s):  
Angela Santonja ◽  
Alfonso Sánchez-Muñoz ◽  
Ana Lluch ◽  
Maria Rosario Chica-Parrado ◽  
Joan Albanell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Response Rate ◽  
Complete Response Rate ◽  
Pathologic Complete Response ◽  
Complete Response ◽  
Cancer Subtypes ◽  
Pathologic Complete Response Rate

Development of prognostic nomograms using institutional data for patients with triple-negative breast cancer

2021 ◽  
Author(s):  
Jie-Yu Zhou ◽  
Kang-Kang Lu ◽  
Wei-Da Fu ◽  
Hao Shi ◽  
Jun-Wei Gu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Predictive Accuracy ◽  
Area Under The Curve ◽  
Disease Free Survival ◽  
Discriminative Ability ◽  
Free Survival ◽  
Disease Free

Background: Triple-negative breast cancer (TNBC) is an aggressive disease. Nomograms can predict prognosis of patients with TNBC. Methods: A total of 745 eligible TNBC patients were recruited and randomly divided into training and validation groups. Endpoints were disease-free survival and overall survival. Concordance index, area under the curve and calibration curves were used to analyze the predictive accuracy and discriminative ability of nomograms. Results: Based on the training cohort, neutrophil-to-lymphocyte ratio, positive lymph nodes, tumor size and tumor-infiltrating lymphocytes were used to construct a nomogram for disease-free survival. In addition, age was added to the overall survival nomogram. Conclusion: The current study developed and validated well-calibrated nomograms for predicting disease-free survival and overall survival in patients with TNBC.

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