Data from Biology and Targetability of the Extended Spectrum of <i>PIK3CA</i> Mutations Detected in Breast Carcinoma
Hope S. RugoKira RaskinaAlexa B. SchrockRussell W. MadisonRyon P. GrafEthan SokolSmruthy SivakumarJessica LeeVirginia FisherGeoffrey R. OxnardHanna Tukachinsky
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<div>AbstractPurpose:<p>Alpelisib is a PI3K alpha (PI3Kα)-selective inhibitor approved for the treatment of hormone receptor–positive/HER2-negative (HR<sup>+</sup>/HER2<sup>−</sup>) <i>PIK3CA</i>-mutated advanced breast cancer (ABC) based on the SOLAR-1 trial, which defined 11 substitutions in exons 7, 9, and 20 in <i>PIK3CA</i> (SOLAR1m). We report alpelisib effectiveness for ABC harboring SOLAR1m, as well as other pathogenic <i>PIK3CA</i> mutations (OTHERm) using comprehensive genomic profiling (CGP).</p>Experimental Design:<p>A total of 33,977 tissue and 1,587 liquid biopsies were analyzed using hybrid capture–based CGP covering the entire coding sequence of <i>PIK3CA</i>. Clinical characteristics and treatment history were available for 10,750 patients with ABC in the deidentified Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB).</p>Results:<p><i>PIK3CA</i>m were detected in 11,767/33,977 (35%) of tissue biopsies, including 2,300 (7%) samples with OTHERm and no SOLAR1m. Liquid biopsy had 77% sensitivity detecting <i>PIK3CA</i>m, increasing to 95% with circulating tumor DNA fraction ≥2%. In patients with HR<sup>+</sup>/HER2<sup>−</sup> ABC and <i>PIK3CA</i>m receiving alpelisib/fulvestrant (ALP+FUL; <i>n</i> = 182) or fulvestrant alone (FUL; <i>n</i> = 119), median real-world progression-free survival (rwPFS) was 5.9 months on ALP+FUL [95% confidence interval (CI): 5.1–7.4] versus 3.1 months on FUL (95% CI: 2.7–3.7; <i>P</i> < 0.0001). In patients with OTHERm, median rwPFS was 4.0 months on ALP+FUL (95% CI: 2.8–10.1) versus 2.5 months on FUL (95% CI: 2.2–3.7; <i>P</i> = 0.0054).</p>Conclusions:<p>CGP detects diverse <i>PIK3CA</i>m in a greater number of patients with ABC than PCR hotspot testing; 20% of patients with <i>PIK3CA</i>m do not have SOLAR1m. These patients may derive benefit from alpelisib.</p><p><i><a href="https://aacrjournals.org/clincancerres/article/doi/10.1158/1078-0432.CCR-22-3411" target="_blank">See related commentary by Tau and Miller, p. 989</a></i></p></div>Keywords:
Triple-negative breast cancer
Objective To study the clinical value of Na+/I-symporter(NIS) expression on triple-negative breast cancer and prediction of 131 I therapeutic effect. Methods 30 samples of triple-negative breast cancer(triple-negative breast cancer,TNBC)were randomly selected as the experimental group,and 30 samples of non-triple negative breast cancer(non-triple-negative breast cancer,non-TNBC)and adjacent tissue of above 30 samples of the triple negative breast cancer,randomly selected as a comparable group,NIS expression was detected by SP immunohistochemical technique and compared with their the differences. Results In triple-negative breast cancer,its adjacent tissue and non-triple negative breast cancer,the positive rates of NIS expression were 66.7 %(20/30),73.3 %(22/30) and 6.7%(2/30) respectively,NIS in Non-triple negative breast cancer group and triple-negative breast cancer group showed no statistic differences(P0.05),triple-negative breast cancer group and its adjacent tissue group showed differences significantly(P0.05),non-three-negative breast cancer group and adjacent tissue of the above triple negative breast cancer tissue group showed differences significantly(P0.05). Conclusion NIS is strongly expressed in a significant proportion of triple-negative breast cancer cells,suggesting a potential role for NIS-directed 131I-radioablative strategies in this patient population.
Triple-negative breast cancer
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OBJECTIVE:To explore the expressions of GST-π,LRP and TopoⅡ in triple negative breast cancer,and study their clinical significance.METHODS:Totally 252 breast cancer patients without preoperative chemotherapy and endocrine therapy were divided into TNBC(triple negative breast cancer) group and the non-TNBC(non-triple-negative breast cancer) group according to the expression of ER,PR and HER-2.The expressions of GST-π,LRP and TopoⅡ were investigated using the immunohisto chemistry method in above two groups.RESULTS:Of all breast cancer patients 18.7%(47/252) were triple negative breast cancer.GST-π expression in the TNBC group was significantly higher than that in the non-TNBC group(χ2=10.466,P=0.001).No significant differences were found in LRP and TopoⅡ expression between the two groups(P=0.678,P=0.777).CONCLUSIONS:TNBC has higher drug resistance that other subtypes.High expression of GST-π may play an important role init.
Triple-negative breast cancer
Clinical Significance
Triple negative
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Triple-negative breast cancer is a high-risk breast cancer with poor survival rate. To date, there is a lack of targeted therapy for this type of cancer. One unique phenomenon is that inflammatory breast cancer is frequently triple negative. However, it is still ambiguous how inflammation influences triple-negative breast cancer growth and responding to chemotherapy. Herein, we investigated the levels of inflammation-associated enzyme, iNOS, in 20 triple-negative breast cancer patients' tumors, and examined its correlation with patients' responses to platinum-based neoadjuvant chemotherapy. Our studies showed that triple-negative breast cancer patients with attenuated iNOS levels in tumor cells after treatment showed better responses to platinum-based neoadjuvant chemotherapy than other triple-negative breast cancer patients. Our further in vitro studies confirmed that induction of proper levels of NO increased the resistance to cisplatin in triple-negative MDA-MB-231 cells. Our data suggest that aberrant high level of iNOS/NO are associated with less effectiveness of platinum-based neoadjuvant chemotherapy in triple-negative breast cancer. Therefore, we propose to monitor iNOS levels as a new predictor for triple-negative breast cancer patient's response to platinum-based neoadjuvant chemotherapy. Moreover, iNOS/NO is considered as a potential target for combination therapy with platinum drugs for triple-negative breast cancer.
Triple-negative breast cancer
Inflammatory breast cancer
Neoadjuvant Therapy
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To investigate the clinical-pathological characteristics of triple negative breast cancer.The clinical-pathological characteristics of 690 breast cancer patients, all females, 127 being estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER)-2 triple negative, were analyzed.The expression rate of P53, a tumor suppressor gene, of the triple negative breast cancer patients was 71.42% (75/127), significantly higher than that of the non-triple negative breast cancer patients (42.56%, P < 0.01), and the expression rate of epidermal growth factor receptor (EGFR) of the triple negative breast cancer was 59.74%, significantly higher than that of the non-triple negative breast cancer patients (22.06%, P = 0.013). The local lymph node metastasis rate of the triple negative breast cancer was 22.22%, significantly higher than that of the non-triple negative breast cancer patients (2.70%, P = 0.048). The 5-year overall survival (OS) rate and 10-year OS rate of he triple negative breast cancer patients were 79.67% and 63.15% respectively, both significantly lower than those of the non-triple negative breast cancer patients (88.59% and 83.28% respectively, both P = 0.001). The 5-year and 10-year disease free survival (DFS) rates of the triple negative breast cancer patients were 77.94% and 62.87% respectively, both significantly lower than those of the non-triple negative breast cancer patients (83.82% and 82.53% respectively, both P = 0.011), especially that within 36 months.Triple negative breast cancer is related with P53 and EGFR expression, and tends to metastasize to local lympho-nodes. The survival rate of triple negative breast cancer patients is significantly lower than that of non-triple negative breast cancer.
Triple-negative breast cancer
Progesterone receptor
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Objective:To analyze the clinicopathological features,prognostic factors of the patients with triple negative breast cancer,and find out effective treatment.Methods:Clinical Data of 510 patients with histopathologically confirmed resectable breast cancer from 2000 to 2005 were analyzed.Of the 510 patients,108(21.2%) were confirmed to be triple-negative breast cancer.The clinical characteristics,local recurrence or distant metastasis,overrall survival of the patients were compared between the triple-negative breast cancer and non-triple negative breast cancer group.Results: Of 510 patients,108(21.2%) had triple negative breast cancer.The rate of local or recurrence or distant metastasis for 5 years in the triple negative breast cancer group(30.8%) was higher than that in the non-triple negative breast cancer group(18.7%,P0.05).The 5-year overrall survival in the triple negative breast cancer group(78.4%) was lower than that in non-triple negative breast cancer group(88.1%,P0.05).Conclusion: Triple negative breast cancer has unique clinicopathological features.Compared with non-triple negative breast cancer,it has an increased possibility of local recurrence and distant metastasis,leading a poorer prognosis.
Triple-negative breast cancer
Distant metastasis
Triple negative
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Abstract Objective:The aim of this study was to investigate the association between triple negative breast cancer (TNBC) susceptibility and single nucleotide polymorphisms (SNPs) of MERIT40(c19orf62)and ANKLE1 genes located in 19p13.1, so as to find the clinical helpful molecular markers and therapeutic targets to the early detection and to guide individualized treatment. Materials and Methods:Totally 252 patients with breast cancer diagnosed and treated in Breast Surgery Department of China-Japan Union Hospital affiliated to Jilin University were taken into the study, Among them,there were 124 cases identified as TNBC by using IHC technique, and others there were 128 cases as non-TNBC. Using common PCR assay and DNA sequencing to detect the SNPs of candidate genes. Finally, the association was analyzed between triple negative breast cancer group and non-triple negative breast cancer group with incidence and impact factors. Results:Three genotypes were detected in rs8170,a SNP of MERIT40 gene located in 19p13.1.The frequencies of CC, CT and TT genotype in the triple negative breast cancer group and non-triple negative breast cancer group were 52.9% vs 93.5%, 41.2% vs 6.5% and 5.9% vs 0.0%.The difference of the distribution of genotypes between two groups was statistically significant (P = 0.004).Three genotypes were detected in rs2363956,a SNP of ANKLE1 gene also located in 19p13.1. The frequencies of TT, GT and GG genotype in the triple negative breast cancer group and non-triple negative breast cancer group were 35.7% vs 38.5%, 42.9% vs 53.8%and 21.4%vs7.7%.The difference of the distribution of genotypes between tow groups was no significant correlation (P = 0.464).Rs2363956 genotypes had obvious correlation with clinical stage (P = 0.005) and lymph node metastasis (P = 0.029) in non-triple negative breast cancer group, but not in triple negative breast cancer group(P = 0.323, P = 0.510).Neither rs8170 nor rs2363956 genotypes had obvious correlation with breast cancer-related immune group, such as EGFR,P53(P>0.05). Logistic regression analysis showed that TT genotype of rs8170 would increase the risk of in TNBC patients (OR = 1.426,95% CI = 1.266-2.872 P = 0.024).There was no significant association between the risk of incidence and the SNPs of ANKLE1 genes. Multivariate Logistic regression analysis showed that the polymorphism of ANKLE1 rs2363956 was an independent prognostic factor with lymph node metastasis and high clinical installments in for non-triple negative breast cancer (OR = 1.228, 95%CI = 1. 104-1.908 P = 0.045), but not for triple negative breast cancer. Conclusions :The rate of incidence is comparatively higher in TNBC patients with TT genotype of MERIT40 rs8170, which may be an important molecular markers to predict the incidence of triple negative breast cancer. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-11.
Triple-negative breast cancer
SNP
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Triple-negative breast cancer
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The aim of the present study was to investigate the expression of estrogen receptor β (ERβ) in triple-negative and triple-positive breast cancer patients, and evaluate its utility as a prognostic factor. Between January 2000 and December 2010, primary tumor tissue samples were collected from 234 subjects, including 107 triple-negative and 127 triple-positive breast cancer patients. The samples were embedded in paraffin and immunohistochemical staining was conducted to determine the expression levels of ERβ. The Kaplan-Meier method was used to analyze patient survival rates. ERβ expression was observed in 38/107 patients (35.5%) with triple-negative breast cancer and 63/127 patients (49.6%) with triple-positive breast cancer. The ERβ expression rate was significantly decreased in the patients with triple-negative breast cancer, as compared with those with triple-positive breast cancer (P=0.03). Analysis of the survival rates indicated that patients with triple-negative breast cancer and positive ERβ expression exhibited poor disease progression-free survival (DFS) compared with those with negative ERβ expression (P=0.021). However, no statistically significant difference was observed in the DFS between the triple-positive breast cancer patients with positive and negative ERβ expression. Therefore, the expression of ERβ varies between triple-negative and triple-positive breast cancer patients. In addition, positive expression of ERβ indicates a poor prognosis in triple-negative breast cancer patients; however, this is not the case for triple-positive breast cancer patients.
Triple-negative breast cancer
Progesterone receptor
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Бұл зерттеужұмысындaКaно моделітурaлы жәнеоғaн қaтыстытолықмәліметберілгенжәнеуниверситетстуденттерінебaғыттaлғaн қолдaнбaлы (кейстік)зерттеужүргізілген.АхметЯссaуи университетініңстуденттеріүшін Кaно моделіқолдaнылғaн, олaрдың жоғaры білімберусaпaсынa қоятынмaңыздытaлaптaры, яғнисaпaлық қaжеттіліктері,олaрдың мaңыздылығытурaлы жәнесaпaлық қaжеттіліктерінеқaтыстыөз университетінқaлaй бaғaлaйтындығытурaлы сұрaқтaр қойылғaн. Осы зерттеудіңмaқсaты АхметЯсaуи университетіндетуризмменеджментіжәнеқaржы бaкaлaвриaт бaғдaрлaмaлaрыныңсaпaсынa қaтыстыстуденттердіңқaжеттіліктерінaнықтaу, студенттердіңқaнaғaттaну, қaнaғaттaнбaу дәрежелерінбелгілеу,білімберусaпaсын aнықтaу мен жетілдіружолдaрын тaлдaу болыптaбылaды. Осы мaқсaтқaжетуүшін, ең aлдыменКaно сaуaлнaмaсы түзіліп,116 студенткеқолдaнылдыжәнебілімберугежәнеоның сaпaсынa қaтыстыстуденттердіңтaлaптaры мен қaжеттіліктерітоптықжұмыстaрaрқылыaнықтaлды. Екіншіден,бұл aнықтaлғaн тaлaптaр мен қaжеттіліктерКaно бaғaлaу кестесіменжіктелді.Осылaйшa, сaпa тaлaптaры төрт сaнaтқa бөлінді:болуытиіс, бір өлшемді,тaртымдыжәнебейтaрaп.Соңындa,қaнaғaттaну мен қaнaғaттaнбaудың мәндеріесептелдіжәнестуденттердіңқaнaғaттaну мен қaнaғaттaнбaу деңгейлерінжоғaрылaту мен төмендетудеосытaлaптaр мен қaжеттіліктердіңрөліaйқын aнықтaлды.Түйінсөздер:сaпa, сaпaлық қaжеттіліктер,білімберусaпaсы, Кaно моделі.
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The nationally-recognized Susquehanna
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