High EGFR protein expression and exon 9 PIK3CA mutations are independent prognostic factors in triple negative breast cancers

11061 Background: Phosphatidylinositol 3-kinase (PI3K)/AKT pathway aberrations are common in breast cancer (BC), PIK3CA mutations being the most common. Mutations are frequently found in hot-spots located in the helical and kinase domains (exons 9 and 20). Reported data is discrepant with regard to prognostic or predictive value of PIK3CA mutations especially in HER2+ve BC. We therefore investigated the frequency and prognostic associations of PIK3CA mutations in HER2+ve and triple negative (TN) primary BC by treated with neoadjuvant therapy. Methods: We prospectively evaluated PIK3CA mutations in the 595 participants of the neoadjuvant Geparsixto study (NCT01426880). The study investigates the effect of adding carboplatin to a liposomal doxorubicin/taxane combination for the treatment of patients with HER2+ve and TN primary BC. All HER2+ve patients received trastuzumab and lapatinib, the TN patients received bevacizumab. HER2, hormone receptors (HR), and Ki67 were centrally assessed. PIK3CAwas genotyped in tumor material from formalin-fixed, paraffin embedded core biopsies taken before therapy using classical Sanger sequencing of exon 9 and 20. Results: From 09/2011 to 11/2012, 595 patients with HER2+ve or TN primary BC have been randomized in the Geparsixto study. Median age was 47 years (range 21-78); most tumors were cT2 (65%); cN0 (57%); ductal invasive (93%), grade 3 (65%); within the HER2+ve group 28% were HR positive. So far, PIK3CA genotype was evaluated in 395 randomized patients - 176 with HER2+ve and 219 with TN disease. Overall, 11.1% were found to have at least one mutation, in HER2+ve: 18.2% and TN BC: 5.5%. An exon 9 mutation was detected in 6.3% of the HER2+ve and 2.7% of the TNBC cases and an exon 20 mutation in 11.9% of the HER2+ve and 3.6% of the TN cases. A mutation in both exons was detected in 2 TN cases. PIK3CAmutations were more frequent in the HER2+ve/HR+ve compared to the HER2+ve/HR-ve group: 22.8% vs 10.6% respectively (p=0.047). Conclusions: PIK3CAmutations are more frequent in HER2+ve then in TN BC which is in line with previous reports. Results on all 595 patients and the correlation with response to therapy (pCR) will be presented at the meeting. The project has been funded within the EU-FP7 project RESPONSIFY No 278659. Clinical trial information: NCT01426880.

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Molecular profiling of triple-negative endometrial cancers (TNEC) and triple-negative breast cancers (TNBC) to reveal unique expression profiles.

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.28_suppl.159 ◽

2015 ◽

Vol 33 (28_suppl) ◽

pp. 159-159

Author(s):

Nathaniel L. Jones ◽

Joanne Xiu ◽

Sandeep K. Reddy ◽

Jason Dennis Wright ◽

William M. Burke ◽

...

Keyword(s):

Breast Cancer ◽

Endometrial Cancer ◽

Protein Expression ◽

Triple Negative ◽

Expression Profiles ◽

Receptor Expression ◽

Mutation Rates ◽

Breast Cancers ◽

Her2 Receptor ◽

Molecular Features

159 Background: “Triple negative” has been used to characterize a subtype of breast cancer that lacks estrogen, progesterone, and HER2 receptor expression. They are aggressive cancers with limited treatment options. It’s unknown if similar phenotype found in other cancer types, like endometrial cancer, harbor similar molecular alterations and prognosis. We aim to compare molecular features between TNEC and TNBC. Methods: A total of 3133 endometrial cancer samples were evaluated by Caris Life Sciences (Phoenix, AZ) from Mar, 2011 to Jul, 2014 by multiplatform profiling, which included a combination of sequencing (Sanger or NGS), protein expression (IHC), and/or gene amplification (CISH or FISH). 545 TNEC and 2049 TNBC were identified based on reported pathology and compared using Fisher exact tests. Results: Compared to an incidence of 15-20% TNBC in breast cancer, 17% (545/3133) TNEC was seen in our cohort, of which 13% were endometrioid, 22% serous, 26% carcinosarcoma, 7% clear cell, and 22% other. Compared with TNBC, TNEC showed 1.9 exonic mutations per case while TNBC showed 1.2 mutations per case. As shown in the table, AR expression is lower in TNEC than TNBC. TP53 mutation was common in both but more frequent in TNBC. While BRCA1/2 mutation rates were similar, low MGMT and ERCC1 were more common in TNEC, suggesting increased aberrant DNA repair. DNA synthesis protein expression was higher in TNEC including TS, RRM1, and TOPO2A, although TNBC had higher TOPO1. PD-1 expression was more common in TNEC suggesting immune pathway involvement. PI3K/AKT/mTor, MAPK and Wnt pathways were more involved in TNEC with greater PTEN, PIK3CA, FBXW7, KRAS and CTNNB1 mutations. Conclusions: Our study reveals significantly higher overall mutation rates in TNEC than TNBC, and specifically higher activations of multiple molecular pathways including PI3K/Akt/mTor, MAPK and Wnt. Further studies are warranted to validate these findings in clinical trials.

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Germline mutations of multiple breast cancer-related genes are differentially associated with triple-negative breast cancers and prognostic factors

Journal of Human Genetics ◽

10.1038/s10038-020-0729-7 ◽

2020 ◽

Vol 65 (7) ◽

pp. 577-587 ◽

Cited By ~ 4

Author(s):

Chihiro Hata ◽

Hirofumi Nakaoka ◽

Yu Xiang ◽

Dong Wang ◽

Anping Yang ◽

...

Keyword(s):

Breast Cancer ◽

Prognostic Factors ◽

Triple Negative ◽

Germline Mutations ◽

Breast Cancers

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Frequency of PIK3CA mutations in HER2+ surgically resected breast cancers in a Hispanic cohort.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e11066 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e11066-e11066

Author(s):

Carlos Munive ◽

Aly Gallo ◽

Silvia P. Neciosup ◽

Franco Doimi ◽

Richard Dyer ◽

...

Keyword(s):

Targeted Therapy ◽

Pik3ca Mutation ◽

Breast Tumors ◽

Breast Cancers ◽

Pik3ca Gene ◽

Pik3ca Mutations ◽

Mutational Status ◽

Pi3k Signaling Pathway ◽

Exon 9 ◽

Exon 20

e11066 Background: PI3K signaling pathway is responsible for balancing cell survival and apoptosis, and plays an important role in the pathogenesis and progression of human breast cancers. Alterations in this pathway could influence the response to targeted therapy. Our aim is to know the frequency of mutations in the PIK3CA gene in HER2+, operable breast tumors in an Andean population. Methods: We include a cohort of 59 patients with HER2+ surgically resected breast cancer that received adjuvant anti-HER2 targeted therapy at the Instituto Nacional de Enfermedades Neoplásicas. Genomic DNA was extracted from Paraffin embedded-formalin fixed tumor samples and mutational status of PIK3CA gene was using PCR-based DNA sequencing Results: At the current date, the median of follow-up in our cohort is 2.4 years and two recurrences have been registered. Four samples were not evaluable for molecular analysis. Mutation in PIK3CA gene was detected in 12 cases (20.3%). In cases where PIK3CA mutation was detected, eight cases (66.7%) had mutations in exon 9 (A1634C/E545A in 6 cases; G1624A/E542K in 1 case and G1633A/E545K in 1 case). Four cases (33.3%) had exon 20 mutated (A3140G/H1047R in all cases). There was not coexistence of mutations in both exons. One case of tumor recurrence had mutation in exon 9. Conclusions: We found similar rates of PIK3CA mutations as described previously to HER2+, breast tumors. A longest follow upwill show the prognostic value of PIK3CA status in our cohort treated with targeted anti-HER2 therapy. [Table: see text]

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PIK3CA mutations in Peruvian patients with HER2-amplified and triple negative non-metastatic breast cancers

Hematology/Oncology and Stem Cell Therapy ◽

10.1016/j.hemonc.2014.09.007 ◽

2014 ◽

Vol 7 (4) ◽

pp. 142-148 ◽

Cited By ~ 4

Author(s):

Carlos A. Castaneda ◽

Marco Lopez-Ilasaca ◽

Joseph A. Pinto ◽

Michelle Chirinos-Arias ◽

Franco Doimi ◽

...

Keyword(s):

Triple Negative ◽

Metastatic Breast ◽

Breast Cancers ◽

Pik3ca Mutations

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PD-L1 Protein Expression in Middle Eastern Breast Cancer Predicts Favorable Outcome in Triple-Negative Breast Cancer

Cells ◽

10.3390/cells10020229 ◽

2021 ◽

Vol 10 (2) ◽

pp. 229

Author(s):

Sandeep Kumar Parvathareddy ◽

Abdul K. Siraj ◽

Saeeda O. Ahmed ◽

Laila Omar Ghazwani ◽

Saud M. Aldughaither ◽

...

Keyword(s):

Breast Cancer ◽

Protein Expression ◽

Mismatch Repair ◽

Triple Negative ◽

Middle Eastern ◽

Strong Association ◽

Treatment Strategies ◽

Prognostic Indicators ◽

Breast Cancers ◽

Ki 67

Programmed cell-death ligand 1 (PD-L1) has been shown to induce potent T-cell mediated anti-tumoral immunity. The significance of PD-L1 expression in the prognosis of breast cancer (BC) remains controversial and its prevalence and prognostic value in breast cancer from Middle Eastern ethnicity is lacking. A total of 1003 unselected Middle Eastern breast cancers were analyzed for PD-L1 expression using immunohistochemistry. PD-L1 expression, seen in 32.8% (329/1003) of cases, was significantly associated with poor prognostic indicators such as younger patients, high-grade tumors, estrogen-receptor (ER)-negative, progesterone-receptor (PR)-negative, and triple-negative breast cancers (TNBC) as well as high Ki-67 index. We also found a significant association between PD-L1 expression and deficient mismatch repair protein expression. No association was found between PD-L1 expression and clinical outcome. However, on further subgroup analysis, PD-L1 expression was found to be an independent marker for favorable overall survival and recurrence-free survival in TNBC. In conclusion, we demonstrated strong association between PD-L1 and mismatch repair deficiency in Middle Eastern BC patients and that PD-L1 overexpression in tumor cells was an independent prognostic marker in TNBCs from Middle Eastern ethnicity. Overall, these findings might help in the development of more appropriate treatment strategies for BC in Middle Eastern population.

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