BRAF: An emerging target for triple-negative breast cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 1099-1099 ◽  
Author(s):  
Joan Albanell ◽  
Julia Andrea Elvin ◽  
Siraj Mahamed Ali ◽  
Alexa Betzig Schrock ◽  
Jon Chung ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Therapy Resistance ◽  
Comprehensive Genomic Profiling ◽  
Er Positive ◽  
Cdh1 Mutation ◽  
Metastatic Sites ◽  
Erbb2 Amplification

1099 Background: A series of reports demonstrating the successful use of BRAF and MEK inhibitors in clinically advanced non-melanoma cancers has recently emerged. BRAF alterations in metastatic breast cancer (mBC) are rare and BRAF is not currently considered a target for the disease. Methods: DNA was extracted from 40 microns of FFPE sections from a series of 10,428 cases of metastatic breast cancer (mBC). Comprehensive genomic profiling (CGP) was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of > 550X for up to 315 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. Results: 135 (1.2%) of the mBC featured alterations in BRAF. The median age of the 135 female patients was 66 years (range 27 to 83 years). The primary tumor was used for CGP in 50 (37%) and from metastatic sites including lymph nodes, liver, bone, lung, brain, adrenal and soft tissue in 85 (67%). Using CDH1 mutation as the definition of lobular mBC, 126 (93%) were ductal and 9 (7%) were lobular histology. Activating BRAF alterations included amplifications (48%), SV mutations (39%) and rearrangements (13%). No (0%) mBC had multiple BRAF GA in the same case. 34% of BRAF SV were V600E and 66% were a wide variety of non-V600E GA. 10 (7.4%) of 135 BRAF mutated mBC featured ERBB2 amplification with 1 (1%) having an ERBB2 SV mutation and 1 (1%) having both ERBB2 amplification and SV GA. Of the 115 BRAF GA cases with known hormone receptor status 71 (62%) were ER negative, 44 (38%) were ER positive and 63 (55%) were triple negative (TNBC). Other targetable genes enriched in mBC with BRAF GA included CDK6 (p = 0.001), HGF (p < 0.001) and MET(p < 0.001). The median TMB was 4.5 with 17 (13%) of cases with TMB > 10 mut/Mb and 7 (5%) of cases with > 20 mut/Mb. Conclusions: BRAF alterations, although uncommon in mBC representing only 1.2% of cases, are enriched in TNBC and feature both targetable base substitutions and rare fusions. BRAF GA may be a rare cause of anti-HER2 therapy resistance in a subset of ERBB2 driven mBC. Targetable genes co-altered with BRAF in mBC include CDK6, HGF and MET. The TMB in BRAF altered mBC is significantly higher than that for mBC in general and indicates potential role for immunotherapy for these patients.

scholarly journals Randomized phase-II evaluation of letrozole plus dasatinib in hormone receptor positive metastatic breast cancer patients

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Devchand Paul ◽  
Svetislava J. Vukelja ◽  
Frankie Ann Holmes ◽  
Joanne L. Blum ◽  
Kristi J. McIntyre ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Acquired Resistance ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Therapy Resistance ◽  
Breast Cancer Patients ◽  
Er Positive

Abstract The non-receptor tyrosine kinase Src activation plays a role in the malignant progression of breast cancer, including development of endocrine therapy resistance and survival of bone metastases. This study investigated whether adding Src kinase inhibitor dasatinib to aromatase inhibitor (AI) therapy improved outcomes in estrogen receptor (ER)-positive, HER2-negative metastatic breast cancer (MBC). Postmenopausal patients with ER-positive, HER2-negative MBC (0–1 prior chemotherapies and no prior AI for MBC) were eligible for this non-comparative, parallel group, phase-II study. Patients were randomized to letrozole (2.5 mg/day PO) alone or with dasatinib (100 mg/day PO). Patients with disease progression on letrozole alone could crossover to dasatinib plus continued letrozole. The primary endpoint was clinical-benefit-rate (CBR; complete response + partial response + stable disease ≥6 months). A total of 120 patients were randomized. The CBR of 71% (95% CI 58–83%) was observed with letrozole + dasatinib versus the projected CBR of the combination of 56%. The CBR of 66% (95% CI 52–77%) with letrozole alone also exceeded the projected CBR of 39% with letrozole alone. The CBR was 23% in the crossover arm of letrozole plus dasatinib in patients progressing on letrozole alone. Median progression-free survival with the combination was 20.1 months and 9.9 months with letrozole alone. Letrozole plus dasatinib was well tolerated, although 26% of patients required dasatinib dose reductions. In this non-comparative phase-II trial, the CBR of 71% and the median PFS of 20.1 months with letrozole + dasatinib are encouraging and suggest that dasatinib may inhibit the emergence of acquired resistance to AI therapy.

scholarly journals Prognostic factors and survival outcomes according to tumor subtype in patients with breast cancer lung metastases

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8298
Author(s):  
Siying Chen ◽  
Jin Yang ◽  
Yang Liu ◽  
Haisheng You ◽  
Yalin Dong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Prognostic Factors ◽  
Metastatic Breast Cancer ◽  
Cancer Patients ◽  
Triple Negative ◽  
Cox Regression ◽  
Lung Metastases ◽  
Metastatic Breast ◽  
Breast Cancer Patients ◽  
Metastatic Sites

Background Reports on the incidence and prognoses of lung metastases when diagnosing breast cancer patients with different subtypes are limited. Our study investigated the effect of molecular sub-typing stratification on the prognoses of lung metastatic breast caner patients. Methods Patients with breast cancer and lung metastases were identified from Surveillance, Epidemiology and End Results population-based data between 2010 and 2015. Univariate and multivariate Cox regression analyses were performed to identify risk factors and prognoses, overall survival (OS) and breast cancer-specific survival for patients with breast cancer lung metastases. Results We identified 6,516 patients with lung metastatic breast cancer, representing 1.7% of the entire cohort and 30.4% of the subset with metastatic disease. This included 2,940 hormone receptor (HR)+/HER2− patients, 852 HR+/HER2+ patients, 547 HR−/HER2+ patients and 983 triple-negative patients. The median OS for all lung metastatic patients was 13 months. Multivariate analysis revealed that those lung metastatic breast cancer patients of older age (>80), black race, with poorly differentiated tumors, carcinoma histology, triple-negative subtype, more metastatic sites and no surgery, and no chemotherapy showed significantly poor survival, both overall and breast cancer-specific. Conclusions Our findings show that molecular sub-type and more metastatic sites might have significant influence on the incidence and prognosis of breast cancer lung metastases. We also identified several prognostic factors that could guide therapy selection in the treatment of lung metastatic patients.

Survival among patients with untreated metastatic breast cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1095-1095
Author(s):  
Jennifer Kay Plichta ◽  
Samantha M. Thomas ◽  
Sarah Sammons ◽  
Susan G.R. McDuff ◽  
Gayle DiLalla ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Triple Negative ◽  
De Novo ◽  
Metastatic Breast ◽  
Disease Characteristics ◽  
Select Patient ◽  
Comorbidity Scores ◽  
Receive Treatment ◽  
Metastatic Sites

1095 Background: Treatments for metastatic breast cancer (MBC) have significantly improved survival for patients who receive treatment, yet data describing the prognosis for untreated patients is lacking. Therefore, we sought to assess the survival outcomes of patients with de novo MBC who did not receive treatment. Methods: Adults with MBC at diagnosis (clinical M1 or pathologic M1) were selected from the NCDB (2010-2016) and stratified based on receipt of treatment (treated = received at least one treatment; untreated = received no treatments). Differences between patient groups were tested using Chi-square tests for categorical variables and t-tests for continuous variables. Overall survival (OS) was estimated using the Kaplan-Meier method for the overall cohort and stratified by select patient and/or disease characteristics, and groups were compared with log-rank tests. Cox Proportional Hazards models were used to identify factors associated with OS in the untreated MBC subgroup. Results: Of the 53,240 patients with de novo MBC, the median age was 61y (IQR 52-71), and the majority had a comorbidity score of 0 (81.2%). Within this cohort, 49,040 (92.1%) received at least one treatment (treated) and 4,200 (7.9%) had no documented treatments (untreated). Untreated patients were more likely to be older (median 68y vs 61y, p < 0.001) and have higher comorbidity scores (p < 0.001). Patients with untreated MBC were more likely to have triple negative disease (17.8% vs 12.6%), and a higher disease burden (≥2 metastatic sites: 38.2% untreated vs 29.2% treated, p < 0.001). The median unadjusted OS in the untreated subgroup was 2.5mo vs 36.4mo in the treated subgroup (p < 0.001). For those who survived at least 1mo post-diagnosis, the median unadjusted OS in the untreated subgroup was 6.9mo vs 37.3mo in the treated subgroup (p < 0.001), which increased to 18.6mo and 40.3mo for those who survived at least 3mo post-diagnosis (p < 0.001). In the untreated population, unadjusted OS varied by breast cancer subtype (median 3.8mo for HR+/HER2-, vs 2.6mo for HER2+, vs 2.1mo for triple negative, p < 0.001) and number of metastatic sites (4.1mo for 1 site, vs 1.8mo for 2 sites, vs 1.1mo for 3 sites, vs 1.2mo for ≥4 sites, p < 0.001). After adjustment, variables associated with a worse OS in the untreated cohort included older age, higher comorbidity scores, higher tumor grade, and triple negative (vs HR+/HER2-) tumor subtype (all p < 0.05), while the number of metastatic sites was not associated with survival; these same findings were also noted when the analysis was limited to those who survived at least 1mo post-diagnosis. Conclusions: Patients with de novo MBC who do not receive treatment are more likely to be older, present with comorbid conditions, and have clinically aggressive disease. Similar to those who do receive treatment, survival in an untreated population is associated with select patient and disease characteristics. However, the prognosis for untreated MBC is dismal.

The contribution of clinical subtype to survival differences among patients with de novo and recurrent metastatic breast cancer (dMBC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1030-1030
Author(s):  
Danielle Marie File ◽  
Tomas Pascual ◽  
Allison Mary Deal ◽  
Amy Wheless ◽  
Elizabeth Claire Dees ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Triple Negative ◽  
De Novo ◽  
Multivariable Analysis ◽  
Metastatic Breast ◽  
Clinical Staging ◽  
Lower Grade ◽  
Significant Difference ◽  
Metastatic Sites

1030 Background: Patients with de novo metastatic breast cancer (dMBC) have superior median overall survival (mOS) compared to recurrent metastatic breast cancer (rMBC). Whether patient characteristics, prior treatment, tumor stage and innate biological differences contribute to this observation is unknown. Methods: Clinical and pathological data from patients diagnosed with MBC from 2011 to 2017 at the University of North Carolina (UNC) was obtained from the prospective UNC Metastatic Breast Cancer Clinical Database (223 dMBC, 607 rMBC). Only patients with known survival status were included. Subtype was determined by hormone receptor (HR) and HER2 staining of the primary tumor. Pathologic staging results were used when available, otherwise clinical staging was used. Patient and tumor characteristics were compared using chi-square testing, and survival outcomes by Cox proportional hazards modeling. Results: 26.9% of patients with MBC presented with dMBC, with significant variation in the ratio of dMBC to rMBC across subtypes. In particular, there were more cases of HER2+ dMBC than rMBC (26.9% vs 14.0%) and fewer cases of triple negative dMBC (20.6% vs 35.3%)(p-value < 0.001). Nearly half of all cases of HR-/HER2+ MBC were de novo (48.2%). dMBC was significantly associated with older age (p = 0.002), lower grade (p = 0.027), higher T and N stage (p < 0.001) and African American race (30% vs 22%, p = 0.022). There was no significant difference in proportion of patients with visceral metastatic disease or in number of metastatic sites at diagnosis. Median follow up was 39 months in both cohorts. mOS was 12 months greater in dMBC than rMBC (34m vs 22m, p < 0.001). These differences were significant across all subtypes except HR+/HER2+. The difference in mOS between dMBC and rMBC was greatest in the HR-/HER2+ subgroup (45m vs 15m, p = 0.006). In multivariable analysis, dMBC remained associated with improved survival (adjusted hazard ratio 0.59, p < 0.001) independent of variables including age, race, subtype, grade and number of metastatic sites at diagnosis. Conclusions: Patients with dMBC have significantly better prognosis than those with rMBC. This improved outcome is in part due to subtype variation, with more triple negative and fewer HER2+ tumors in rMBC, however these differences largely remained when stratified by subtype. In multivariable analysis, de novo presentation of MBC remained an independently significant contributor to longer survival. Further investigation should focus on biologic differences between dMBC and rMBC.

scholarly journals A Combination of Targeted Therapy with Chemotherapy Backbone Induces Response in a Treatment-Resistant Triple-Negative MCL1-Amplified Metastatic Breast Cancer Patient

2016 ◽  
Vol 9 (1) ◽  
pp. 112-118 ◽  
Author(s):  
Siraj M. Ali ◽  
Jessica Watson ◽  
Kai Wang ◽  
Jon H. Chung ◽  
Caitlin McMahon ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Hospice Care ◽  
Treatment Initiation ◽  
Clinical Care ◽  
Metastatic Breast ◽  
Genomic Profiling ◽  
Treatment Resistant ◽  
Bcl2 Family ◽  
Comprehensive Genomic Profiling

After failure of anthracycline- and platinum-based therapy, no effective therapies exist for management of metastatic triple-negative breast cancer (TNBC). We report a case of metastatic TNBC harboring MCL1 amplification, as identified by comprehensive genomic profiling in the course of clinical care. MCL1 is an antiapoptotic gene in the BCL2 family, and MCL1 amplification is common in TNBC (at least 20%). A personalized dose-reduced regimen centered on a combination of sorafenib and vorinostat was implemented, based on preclinical evidence demonstrating treatment synergy in the setting of MCL1 amplification. Although hospice care was being considered before treatment initiation, the personalized regimen yielded 6 additional months of life for this patient. Further rigorous studies are needed to confirm that this regimen or derivatives thereof can benefit the MCL1-amplified subset of TNBC patients.

scholarly journals The Incidence of Brain Metastases Among Patients with Metastatic Breast Cancer: A Systematic Review and Meta-Analysis

2020 ◽  
Author(s):  
Markus Kuksis ◽  
Yizhuo Gao ◽  
William Tran ◽  
Christianne Hoey ◽  
Alex Kiss ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Systematic Review ◽  
Metastatic Breast Cancer ◽  
Brain Metastases ◽  
Triple Negative ◽  
Screening Program ◽  
Meta Analysis ◽  
Metastatic Breast ◽  
Breast Cancer Brain Metastasis

Abstract Background Patients with metastatic breast cancer (MBC) are living longer, but development of brain metastases often limits their survival. We conducted a systematic review and meta-analysis to determine the incidence of brain metastases in this patient population. Methods Articles published from January 2000 to January 2020 were compiled from four databases using search terms related to: breast cancer, brain metastasis, and incidence. The overall and per patient-year incidence of brain metastases were extracted from studies including patients with HER2+, triple negative, and hormone receptor (HR)+/HER2- MBC; pooled overall estimates for incidence were calculated using random effects models. Results 937 articles were compiled, and 25 were included in the meta-analysis. Incidence of brain metastases in patients with HER2+ MBC, triple negative MBC, and HR+/HER2- MBC was reported in 17, 6, and 4 studies, respectively. The pooled cumulative incidence of brain metastases was 31% for the HER2+ subgroup (median follow-up: 30.7 months, IQR: 24.0 – 34.0), 32% for the triple negative subgroup (median follow-up: 32.8 months, IQR: 18.5 – 40.6), and 15% among patients with HR+/HER2- MBC (median follow-up: 33.0 months, IQR: 31.9 – 36.2). The corresponding incidences per patient-year were 0.13 (95% CI: 0.10 – 0.16) for the HER2+ subgroup, 0.13 (95%CI: 0.09 – 0.20) for the triple negative subgroup, and only 0.05 (95%CI: 0.03 – 0.08) for patients with HR+/HER2- MBC. Conclusion There is high incidence of brain metastases among patients with HER2+ and triple negative MBC. The utility of a brain metastases screening program warrants investigation in these populations.

scholarly journals Staging Investigations in Asymptomatic Early Breast Cancer Patients at the Cancer Centre of Southeastern Ontario

2021 ◽  
Vol 28 (3) ◽  
pp. 2190-2198
Author(s):  
Dalia Kamel ◽  
Veronica Youssef ◽  
Wilma M. Hopman ◽  
Mihaela Mates
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Adjuvant Chemotherapy ◽  
Early Breast Cancer ◽  
Triple Negative ◽  
Metastatic Breast ◽  
Receptor Status ◽  
Cancer Centre ◽  
Radiological Staging

Background: In 2012, the American Society for Clinical Oncology (ASCO) identified five key opportunities in oncology to improve patient care, recommending against imaging tests for the staging of patients with early breast cancer (EBC) at low risk for metastases. Similarly, the European Society of Medical Oncology (ESMO) guideline does not support radiological staging in asymptomatic EBC (aEBC). The purpose of this study was to assess local practice and outcomes of staging investigations (SIs) in aEBC at the Cancer Centre of Southeastern Ontario (CCSEO). Methods: A retrospective electronic and paper chart review was undertaken to identify all aEBC patients treated at our institution between January 2012 and December 2014. Patients with pathological staging of T1-T2 and N0-1 with any receptor status were included. We collected patient demographics, treatment and pathologic tumor characteristics. The use and outcomes of initial and follow-up SIs were recorded. Data were analyzed to determine associations between the use of SIs and clinical characteristics (chi-square tests, independent samples t-tests and Mann–Whitney U tests). Results: From 2012 to 2014, 295 asymptomatic EBC patients were identified. The mean age was 64, 81% were postmenopausal and 76% had breast conserving surgery. Stage distribution was as follows: stage I 42%, stage IIA 37% and stage IIB 21%. Receptor status was as follows: ER+ 84%, HER2+ 13% and triple negative 12%. Adjuvant chemotherapy was received by 36%, Trastuzumab by 10% and endocrine therapy by 76% of patients. Baseline SIs were performed in 168 patients (57%) for a total of 332 tests. Overt metastatic disease was found in five patients (one bone scan and four CT scans). Seventy-one out of the 168 patients (42%) who received initial staging imaging underwent 138 follow-up imaging tests, none of which were diagnostic for metastases. Nine patients with suspicious CT findings underwent biopsies, of which four were malignant (one metastatic breast cancer and three new primaries). Factors significantly associated with SI were as follows: younger age (p = 0.001), premenopausal status (p = 0.01), T2 stage (p < 0.001), N1 stage (p < 0.001), HER2 positive (p < 0.001), triple negative status (p = 0.007) and use of adjuvant chemotherapy (p < 0.001). Conclusions: Over a 3-year period at our institution, more than 50% of aEBC patients underwent a total of 470 initial and follow-up staging tests, yielding a cancer diagnosis (metastatic breast cancer or second primary cancer) in four patients. We, therefore, conclude that routine-staging investigations in aEBC patients have low diagnostic value, supporting current guidelines that recommend against the routine use of SI in this population.

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