Next-generation sequencing (NGS) in metastatic breast cancer (mBC) patients: Translation from sequence data into clinical practice.

2015 ◽  
Vol 33 (28_suppl) ◽  
pp. 133-133 ◽  
Author(s):  
Raphael Brandao Moreira ◽  
Renata Peixoto ◽  
Tercia Tarciane Soares de Sousa ◽  
Marcelo Cruz ◽  
Fernando Maluf ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Sequence Data ◽  
Objective Response ◽  
Metastatic Breast ◽  
Genomic Alteration ◽  
Histologic Subtype ◽  
Mutational Profiling ◽  
Number Of Patients ◽  
Her 2

133 Background: A considerable number of patients with mBC progress after exhausting all approved standard therapies but maintain an adequate performance status and could be candidates for further treatment. We aim at reviewing our experience with the use of a NGS platform in refractory mBC and its clinical utility. Methods: We retrospectively reviewed demographics, NGS results, and the suggested therapies received by patients undergoing NGS (Foundation Medicine, Cambridge, MA, USA): exonic sequencing of 315 genes and selective intronic sequencing from 28 genes for refractory mBC. Co-primary endpoints were the percentage of patients with targeted therapy options uncovered by mutational profiling and the percentage of them who received genotype-directed therapy. Results: Samples from 20 patients were tested. Histologic subtype consisted of triple negative (50%), HER 2 +, hormonal receptor [HR] - 15%, HR + and HER 2 - (35%). A targetable genomic alteration was identified in 14 (70%) patients, most frequently in TP53 (11 [55%]), PIK3CA (8 [40%]), FGFR1 (4 [20%]), CCND1 (3 [15%]), PTEN (3[15%]) and BRCA2 (2[10%]). Therapy could be personalized in 9 (45%) of 14 patients. Of the 9 patients who were received targeted therapy, 7 (77%) had an objective response and had stable disease for more than 3 months. Conclusions: Mutational profiling using a targeted NGS panel identified potentially actionable alterations in the majority of advanced breast cancer patients. The assay provided clinical benefit in 35% of the patients.

Next-generation sequencing (NGS) in metastatic gastrointestinal cancer (mGIC) patients: Translation from sequence data into clinical practice.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 72-72 ◽  
Author(s):  
Raphael Brandao Moreira ◽  
Matheus Bongers Alessandretti ◽  
Carina Mina Abrahao ◽  
Aline Da Rocha Lino ◽  
Tarcia Tarciane Soares de Sousa ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Gastrointestinal Cancer ◽  
Sequence Data ◽  
Performance Status ◽  
Objective Response ◽  
Genetic Alterations ◽  
Mitogen Activated Protein Kinase ◽  
Primary Tumors ◽  
Mutational Profiling ◽  
Number Of Patients

72 Background: A considerable number of patients with mGIC progress after exhausting all approved standard therapies but maintain an adequate performance status and could be candidates for further treatment. We aim at reviewing our experience with the use of a NGS platform in refractory mGIC and its clinical utility. Methods: We retrospectively reviewed demographics, NGS results, and the suggested therapies received by patients undergoing NGS (Foundation Medicine, Cambridge, MA, USA): exonic sequencing of 236 genes and selective intronic sequencing from 19 genes for refractory mGIC. Co-primary endpoints were the percentage of patients with targeted therapy options uncovered by mutational profiling and the percentage of them who received genotype-directed therapy. Results: Samples from 32 patients were tested. Primary tumors consisted of colorectal adenocarcinoma (37,5%), pancreatic adenocarcinoma (31,2%), gastric adenocarcinoma (12,5%), cholangiocarcinoma (12,5%) and hepatocellular carcinoma (6%). Most patients (87,5%) were found to harbor potentially actionable genetic alterations involving mitogen-activated protein kinase (93,7%), phosphatidylinositol 3-kinase-AKT (18,7%), p53 (50%) and cell-cycle regulation (9%) pathways. Of the 6 patients who received the suggested targeted therapy, 4 achieved an objective response. Conclusions: Mutational profiling using a targeted NGS panel identified potentially actionable alterations in the majority of advanced gastrointestinal cancer patients. The assay provided clinical benefit in 12% of the patients.

scholarly journals How shall we treat locally advanced triple negative breast cancer?

F1000Research ◽  
2020 ◽  
Vol 8 ◽  
pp. 1649
Author(s):  
Paulo Luz ◽  
David Dias ◽  
Ana Fortuna ◽  
Luis Bretes ◽  
Beatriz Gosalbez
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Locally Advanced ◽  
Surrogate Marker ◽  
Metastatic Breast ◽  
Complete Response ◽  
Number Of Patients ◽  
Her 2 ◽  
Near Future

Triple negative breast cancer (TNBC) has been shown to respond to neoadjuvant chemotherapy (NACT). It has been established that achieving pathological complete response (pCR) for certain aggressive subtypes of breast cancer, including HER-2 (over-expressed) and TNBC, provides an important surrogate marker for predicting long-term clinical response and survival outcomes. How to increase the number of patients that achieve pCR remains challenging. Platinum-based NACT seems to be part of the solution and capecitabine, an active drug in metastatic breast cancer, but not a standard one in earlier stages may have found its place in the adjuvant setting. In the near future immunotherapy can play a role in early TNBC

Real world experience of palbociclib in hormone receptor-positive metastatic breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18094-e18094 ◽  
Author(s):  
Faizan Malik ◽  
Naveed Ali ◽  
Syed Imran Mustafa Jafri ◽  
Mark L. Sundermeyer ◽  
Michael Jeffrey Seidman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Side Effects ◽  
Real World ◽  
Hormone Receptor ◽  
Objective Response ◽  
Metastatic Breast ◽  
Hormone Receptor Positive ◽  
Her 2 ◽  
Grade 3

e18094 Background: Palbociclib has been approved as a first line therapy in hormone-receptor positive (HR+) and HER-2 negative metastatic breast cancer(MBC) manifesting significant improvement in progression free survival (PFS). We studied this drug in a community setting. The endpoints were estimated PFS, objective response, toxicities and patient outcomes. Methods: This was a single-center, retrospective study of HR+MBC patients receiving palbociclib after its FDA approval. 22 patients were selected Results: A total of 22 patients were included (Male = 2, Female = 20). Median age was 60-years (range, 49-84). About 90% patients had received at least one previous therapy and the median number was 1.5. 13% patients were on fulvestrant, 86% on letrozole and 4.5% on exemestane. About 64% of patients had ECOG status of ≥ 1. Median duration of palbociclib treatment was 5-months, therefore, an estimated PFS at 18-months was 50%. 4.5% patients attained complete response. 22% patients achieved partial response, 22% had stable disease and 50% patients demonstrated disease progression. 72% patients had neutropenia, of which 45% were grade ≥ 3. Thrombocytopenia and anemia were common (63% and 58%, respectively) but grade ≥ 3 thrombocytopenia or anemia was not observed. 50% patients required dose reductions and 18% required drug cessation owing to side effects. Conclusions: PFS was much lower as compared to actual trials in our real-world experience. Despite, several interesting observations were good objective response rates in males and HER-2+ patients underscoring its potential clinical efficacy in these subsets. Furthermore, apart from myelosuppressive side effects, pneumonitis was observed in one patient necessitating vigilance in clinical practice

scholarly journals Molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Zongbi Yi ◽  
Guohua Rong ◽  
Yanfang Guan ◽  
Jin Li ◽  
Lianpeng Chang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Targeted Therapy ◽  
Partial Response ◽  
Objective Response ◽  
Metastatic Breast ◽  
Complete Response ◽  
Her2 Amplification ◽  
Cox Regression Analysis ◽  
Molecular Landscape

Abstract Human epidermal growth factor receptor 2 (HER2) protein overexpression or gene amplification is an important predictive biomarker for identifying patients with breast cancer, who may benefit from HER2-targeted therapy. However, little is known about the molecular landscape and efficacy of HER2-targeted therapy in patients with HER2-mutated metastatic breast cancer. We analysed the HER2 mutation features of 1184 patients with invasive breast cancer. In addition, a single-arm, prospective, phase-II study (NCT03412383) of pyrotinib was conducted in patient with metastatic HER2 amplification-negative, mutation-positive breast cancer. Peripheral blood was collected from each patient and circulating tumour DNA (ctDNA) sequencing was performed using a 1021 gene panel. HER2 mutations were detected in 8.9% (105/1184) of patients. The HER2 amplification-positive patients had a higher mutation frequency than the HER2 amplification-negative patients (19.5% vs. 4.8%, P < 0.001). A multivariate Cox regression analysis indicated that patients with HER2 mutations had a shorter progression-free survival (PFS) than HER2 wild-type patients (median PFS 4.7 months vs. 11.0 months, hazard ratio 2.65, 95% confidence interval 1.25–5.65, P = 0.011). Ten HER2 amplification-negative, mutation-positive patients who received pyrotinib monotherapy were ultimately included in the efficacy analysis. The median PFS was 4.9 months. The objective response rate (complete response + partial response) was 40.0% and the clinical benefit rate (complete response + partial response + stable disease over 24 weeks) was 60%. In conclusion, a HER2 gene mutation analysis is potentially useful to identify biomarkers of trastuzumab resistance in HER2 amplification-positive patients. Patients with HER2-mutated, non-amplified metastatic breast cancers may benefit from pyrotinib.

scholarly journals How shall we treat locally advanced triple negative breast cancer?

F1000Research ◽  
2019 ◽  
Vol 8 ◽  
pp. 1649
Author(s):  
Paulo Luz ◽  
David Dias ◽  
Ana Fortuna ◽  
Luis Bretes ◽  
Beatriz Gosalbez
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Locally Advanced ◽  
Surrogate Marker ◽  
Metastatic Breast ◽  
Complete Response ◽  
Number Of Patients ◽  
Her 2

Triple negative breast cancer (TNBC) has been shown to respond to neoadjuvant chemotherapy (NACT). It has been established that achieving pathological complete response (pCR) for certain aggressive subtypes of breast cancer, including HER-2 (over-expressed) and TNBC, provides an important surrogate marker for predicting long-term clinical response and survival outcomes. How to increase the number of patients that achieve pCR remains challenging. Platinum-based NACT seems to be part of the solution and capecitabine, an active drug in metastatic breast cancer, but not a standard one in earlier stages may have found its place in the adjuvant setting.

Impact of adjuvant trastuzumab on outcomes of HER2-positive breast cancer patients treated with HER2-targeted therapy in the metastatic setting.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 527-527
Author(s):  
Rashmi Krishna Murthy ◽  
Ankur Varma ◽  
Priyankana Mishra ◽  
Kenneth R. Hess ◽  
Elliana J. Young ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Early Stage ◽  
Menopausal Status ◽  
Metastatic Breast ◽  
Hazard Ratio ◽  
Adjuvant Setting ◽  
Her2 Breast Cancer ◽  
Metastatic Setting ◽  
Her 2

527 Background: Trastuzumab (T) was approved for the adjuvant treatment of women with early-stage, HER-2 overexpressing (HER2+) breast cancer in 2006. There are limited data outlining the outcomes of patients with HER2+ breast cancer who receive adjuvant T-based therapy and then receive T and/or lapatinib in the metastatic setting. Methods: We identified 540 patients with HER2+ breast cancer treated with T or lapatinib as part of their first-line treatment for metastatic disease from 01/1997 to 11/2011. HER-2 positivity was assessed by immunohistochemistry (score, 3+) or fluorescence in situ hybridization (HER2/CEP17 ratio ≥ 2). We excluded 17 patients from this analysis because they were either lost to follow-up or received less than 2 cycles of therapy at the institution. Statistical analyses were performed using the chi-square test to compare proportions between groups and the Cox proportional hazards regression analysis to compare survival times and estimate the corresponding hazard ratio with 95% confidence interval. Results: Of the 523 patients eligible for analysis, 76 patients had received T in the adjuvant setting and 447 had not. In the group who did not receive adjuvant T, 48% (213/447) of patients achieved a complete or partial response (CR/PR), whereas only 13% (14/76) achieved a CR/PR in the adjuvant T group (P<.0001). After adjustment for age, disease-free interval, post-menopausal status, stage at presentation, ER/PR status, and nuclear grade, the odds ratio was 0.27 (CI 0.13 - 0.56, p = 0.0004). Overall survival from first evidence of metastasis was significantly longer in the group who did not receive adjuvant T (39 months vs. 24 months, HR = 1.8, 95% CI 1.3-2.4). For OS, the adjusted hazard ratio was 1.5 (CI 1.04 - 2.1, p = 0.029). Age, DFI and stage were also significant predictors of OS. Conclusions: Patients with HER2+ metastatic breast cancer who were T naive, had a higher response rate (CR/PR) to front line HER2 targeted therapy and a longer OS compared to patients with metastatic HER2+ breast cancer who received T in the adjuvant setting. These findings highlight the importance of recognizing a pre-treated population and calls for further research in this area.

Impact of Her-2-Targeted Therapy on Overall Survival in Patients With Her-2 Positive Metastatic Breast Cancer

2013 ◽  
Vol 19 (2) ◽  
pp. 149-155 ◽  
Author(s):  
Anna S. Berghoff ◽  
Zsuzsanna Bago-Horvath ◽  
Peter Dubsky ◽  
Margaretha Rudas ◽  
Ursula Pluschnig ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Metastatic Breast Cancer ◽  
Targeted Therapy ◽  
Metastatic Breast ◽  
Her 2

Correlation of FcγR IIa-H131R and IIIa-V158F polymorphisms and clinical outcome of trastuzumab in both neoadjuvant and metastatic setting in patients with HER-2 positive breast cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 1100-1100
Author(s):  
K. Tamura ◽  
C. Shimizu ◽  
F. Koizumi ◽  
T. Kouno ◽  
N. Katsumata ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Clinical Outcome ◽  
Objective Response ◽  
Metastatic Breast ◽  
Complete Response ◽  
Nucleotide Polymorphisms ◽  
Metastatic Setting ◽  
Dependent Cell ◽  
Her 2 ◽  
First Time

1100 Background: The antibody dependent cell mediated cytotoxicity (ADCC) affects an efficacy of Immunoglobulin G1 antibody, including trastuzumab which is a humanized anti-HER-2 monoclonal antibody, through fragment C receptor (FcγR) polymorphisms. One report suggested that allotype of two kinds of FcγR single nucleotide polymorphisms (SNPs) are associated with clinical outcome of patients (pts) with metastatic breast cancer (BC) who received combination trastuzumab with taxane. Ethnic difference was reported in frequency of these SNPs between Western and Asian pts. The objective of this prospective study was to evaluate whether these SNPs are associated with pathological complete response (pCR) in neoadjuvant (N) setting with pts who received trastuzumab based chemotherapy, and objective response (OR) in metastatic (M) setting in pts who received single trastuzumab. Methods: Eligible criteria include HER-2 positive BC, chemotherapy-naïve, measurable disease, PS 0–2 and adequate organ functions. Pts in N setting received standard FEC (5-fluorouracil/epirubicin/cyclophosphamide q3w for 4cycles followed by weekly paclitaxel/trastuzumab for 12 weeks. Pts in M setting received single trastuzumab q1w until progression. 384 SNPs of different FcγR loci were assessed from genomic DNA extracted from peripheral blood by GOLDEGATE beads array (illumina Co.). Results: Nineteen operable and 36 metastatic HER-2 positive BC pts have been enrolled in each N and M setting, respectively. pCR in N setting was 26.3%, and OR in M setting was 22.2%. The frequencies of FcγRIIa131 genotypes were H/H 43%, H/R 49%, R/R 8%, and that of FcγRIIIa158 were V/V 43%, V/F 47%, F/F 10%, respectively. 131H/H genotype was significantly correlated with pCR (p = 0.0034) and OR (p = 0.037). 158V/V genotype had a tendency to be correlated with pCR (p = 0.067) and was significantly correlated with OR (p = 0.037). The median PFS was 8.9 months for pts with 131H/H and 3.8 months for R carriers (H/R or R/R). Conclusions: Our data for the first time suggest that these two SNPs predict pCR to trastuzumab based chemotherapy in N setting, and OR to single trastuzumab in M setting. No significant financial relationships to disclose.

Serum TIMP-1 and Response to the Aromatase Inhibitor Letrozole Versus Tamoxifen in Metastatic Breast Cancer

2008 ◽  
Vol 26 (16) ◽  
pp. 2653-2658 ◽  
Author(s):  
Allan Lipton ◽  
Kim Leitzel ◽  
Hilary A. Chaudri-Ross ◽  
Dean B. Evans ◽  
Suhail M. Ali ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Aromatase Inhibitor ◽  
Objective Response ◽  
Elevated Serum ◽  
Metastatic Breast ◽  
Enzyme Linked Immunosorbent Assay ◽  
Time To Treatment ◽  
Her 2 ◽  
Pretreatment Serum

Purpose To determine the effect of elevated serum TIMP-1 on the response of patients with metastatic breast cancer to an aromatase inhibitor versus tamoxifen. Patients and Methods Five hundred twenty-two patients estrogen receptor–positive metastatic breast cancer were randomly assigned to receive first-line hormone therapy with letrozole or tamoxifen. Serum tissue inhibitor of metalloproteinases-1 (TIMP-1) levels were measured using an enzyme-linked immunosorbent assay. Results Pretreatment serum TIMP-1 was elevated in 120 (23%) of 522 patients. Patients with elevated serum TIMP-1 had a significantly reduced objective response rate (19.2% v 30.6%; odds ratio, 0.54; P = .01), duration of response (median, 15.5 v 26.2 months; P = .001), time to treatment progression (TTP; median, 4.5 v 9.2 months; HR, 1.78; P = .0001), time to treatment failure (median, 3.5 v 9.0 months; HR, 1.77; P = .0001), and overall survival (median, 20.3 v 35.8 months; HR, 1.77; P = .0001) compared with patients with normal pretreatment TIMP-1 levels. Letrozole was superior to tamoxifen in both the normal serum TIMP-1 group (median TTP, 11.8 v 8.6 months; P = .003) and in the elevated serum TIMP-1 group (median, 6.1 v 3.2 months; P = .03) In multivariate analysis, elevated serum TIMP-1 remained an independent predictor of both shorter TTP (HR, 1.46; P = .002) and survival (HR, 1.44; P = .002), as did serum HER-2. Combined analysis of both serum TIMP-1 and HER-2/neu conferred additional ability to predict significantly different clinical outcomes compared to using either biomarker alone. Conclusion Patients with elevated pretreatment serum TIMP-1 had a significantly reduced response and survival. Serum TIMP-1 was an independent predictive and prognostic factor. Blockade of TIMP-1 and HER-2/neu activity may be beneficial in a subset of patients with breast cancer.

scholarly journals Russian multicenter experience of using talazoparib in the treatment of patients with BRCA-associated metastatic breast cancer

2020 ◽  
pp. 143-146
Author(s):  
T. Yu. Semiglazova ◽  
E. V. Lubennikova ◽  
L. V. Bolotina ◽  
R. V. Orlova ◽  
F. V. Moiseenko ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Targeted Therapy ◽  
Disease Control ◽  
Metastatic Disease ◽  
Triple Negative ◽  
Objective Response ◽  
Metastatic Breast ◽  
Biological Subtype ◽  
Triple Negative Subtype

Introduction. The presence of a germinal BRCA mutation occurs in 3–4% of all breast cancer (BC) patients with various biological subtypes, but significantly with a high frequency in patients with a triple negative biological subtype (in 10–20% of cases). For the treatment of patients with HER2-negative metastatic breast cancer associated with gBRCA mutation, the effectiveness of biologically targeted drugs from the group of PARP inhibitors (olaparib and talazoparib) has been proven.Purpose. Comparison of the results of our experience with the use of talazoparib in patients with HER2-gBRCA+ + mBC with the data of the EMBRACA registration study.Materials and methods. As part of the multicenter compassionate use program (CUP) with the support of Pfizer, 24 patients with HER2-negative metastatic gBRCA-associated mutation metastatic breast cancer (HER2-gBRCA+ breast cancer) received biologically targeted therapy with the PARP inhibitor talazoparib at a standard oral dose of 1 mg per day for vital indications . The average age of patients with HER2-gBRCAm+ breast cancer was 50 years (29–90 years).Results. Objective response (OR) was registered in 29% of cases, disease control (OR+stabilization) – in 71% of cases. The median progression-free survival (PFS) was 6.5 months (95% CI [3–10]). Objective response, disease control, and median PFS were evaluated depending on the biological subtype, the number of lines of previous therapy, and the presence of platinum-containing agents in the anamnesis.Objective response and disease control were evaluated depending on the biological subtype: in patients with ER+HER2-mBC versus patients with triple negative subtype, OR was 33% vs 22%, and disease control was 83% vs 61%, respectively. In the presence of < 3 vs ≥ 3 lines of therapy for metastatic disease in the anamnesis, OR was 31% vs 12.5%, disease control – 75% vs 50% of cases, respectively. In the presence or absence of platinum-containing agents in the anamnesis, OR was observed in 22% vs 33% of cases, and disease control – 67% vs 67%, respectively.In patients with the luminal subtype versus patients with the triple negative subtype, the PFS was 9 months vs 5 months, respectively (HR = 0.705; 95% CI [0.231–2.147]; p = 0.5208). Median PFS in the presence of <3 vs ≥3 lines of therapy for metastatic disease in the anamnesis was 9 months vs 4 months, respectively (HR = 4,216; 95% CI [1,334–13,327]; p = 0.0056). In the presence or absence of platinum-containing agents in previous lines of therapy 5 months vs 9.5 months, respectively (HR =1.484; 95% CI [0.48–4.582]; p = 0.4750).During the treatment with talazoparib adverse events of the 3rd-4th grades were observed in 5 patients (20,8%). These include moderate and severe anemia in 3 patients (12.5%), thrombocytopenia in 1 patient (4%), and neutropenia in 1 patient (4%). The majority of patients (79,5%), which received talazoparib, did not require dose adjustment. The need to reduce the dose to 0.75 mg was noted in 3 patients (12.5%), to 0.5 mg – in 2 patients (8%). Hemotransfusion was performed in 3 patients. For effective therapy safety management regular monitoring of blood parameters is necessary.Conclusion. Thus, targeted therapy with talazoparib is an effective treatment option for HER2-gBRCA+ mBC.

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