Abstract A21: Compound PIK3CA mutations support a mutational dose-response model for oncogene activation and response to PI3K inhibitor targeted therapy in breast cancer

2020 ◽  
Author(s):  
Neil Vasan ◽  
Jared Johnson ◽  
Hong Shao ◽  
Pedram Razavi ◽  
Alexander Gorelick ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Dose Response ◽  
Pi3k Inhibitor ◽  
Response Model ◽  
Pik3ca Mutations ◽  
Oncogene Activation

scholarly journals Double PIK3CA mutations in cis enhance PI3Kα oncogene activation and sensitivity to PI3Kα inhibitors in breast cancer

2019 ◽  
Vol 30 ◽  
pp. iii1 ◽  
Author(s):  
N. Vasan ◽  
P. Razavi ◽  
J.L. Johnson ◽  
H. Shao ◽  
E. Reznik ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Pik3ca Mutations ◽  
Oncogene Activation ◽  
In Cis

scholarly journals PIK3CA and MAP3K1 alterations imply luminal A status and are associated with clinical benefit from pan-PI3K inhibitor buparlisib and letrozole in ER+ metastatic breast cancer

2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Mellissa J. Nixon ◽  
Luigi Formisano ◽  
Ingrid A. Mayer ◽  
M. Valeria Estrada ◽  
Paula I. González-Ericsson ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Clinical Benefit ◽  
Metastatic Breast ◽  
Response To Therapy ◽  
Pi3k Inhibitor ◽  
Breast Cancer Cell Lines ◽  
Luminal A ◽  
Pik3ca Mutations ◽  
Pi3k Inhibitors

Abstract Clinical trials have demonstrated the efficacy of combining phosphoinositide 3-kinase (PI3K) inhibitors with endocrine therapies in hormone therapy-refractory breast cancer. However, biomarkers of PI3K pathway dependence in ER+ breast cancer have not been fully established. Hotspot mutations in the alpha isoform of PI3K (PIK3CA) are frequent in ER+ disease and may identify tumors that respond to PI3K inhibitors. It is unclear whether PIK3CA mutations are the only biomarker to suggest pathway dependence and response to therapy. We performed correlative molecular characterization of primary and metastatic tissue from patients enrolled in a phase Ib study combining buparlisib (NVP-BKM-120), a pan-PI3K inhibitor, with letrozole in ER+, human epidermal growth factor-2 (HER2)-negative, metastatic breast cancer. Activating mutations in PIK3CA and inactivating MAP3K1 mutations marked tumors from patients with clinical benefit (≥6 months of stable disease). Patients harboring mutations in both genes exhibited the greatest likelihood of clinical benefit. In ER+ breast cancer cell lines, siRNA-mediated knockdown of MAP3K1 did not affect the response to buparlisib. In a subset of patients treated with buparlisib or the PI3Kα inhibitor alpelisib each with letrozole where PAM50 analysis was performed, nearly all tumors from patients with clinical benefit had a luminal A subtype. Mutations in MAP3K1 in ER+ breast cancer may be associated with clinical benefit from combined inhibition of PI3K and ER, but we could not ascribe direct biological function therein, suggesting they may be a surrogate for luminal A status. We posit that luminal A tumors may be a target population for this therapeutic combination.

scholarly journals Aptamer-protamine-siRNA nanoparticles in targeted therapy of ErbB3 positive breast cancer cells

2020 ◽  
Vol 590 ◽  
pp. 119963
Author(s):  
Xiangshang Xu ◽  
Li Li ◽  
Xiaolan Li ◽  
Deding Tao ◽  
Peng Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Positive Breast Cancer

scholarly journals Single Cell Genetic Profiling of Tumors of Breast Cancer Patients Aged 50 Years and Older Reveals Enormous Intratumor Heterogeneity Independent of Individual Prognosis

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3366
Author(s):  
Anna-Sophie Liegmann ◽  
Kerstin Heselmeyer-Haddad ◽  
Annette Lischka ◽  
Daniela Hirsch ◽  
Wei-Dong Chen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Copy Number ◽  
Genome Instability ◽  
Single Cells ◽  
Gene Mutations ◽  
Intratumor Heterogeneity ◽  
Breast Cancer Patients ◽  
Luminal A ◽  
Pik3ca Mutations

Purpose: Older breast cancer patients are underrepresented in cancer research even though the majority (81.4%) of women dying of breast cancer are 55 years and older. Here we study a common phenomenon observed in breast cancer which is a large inter- and intratumor heterogeneity; this poses a tremendous clinical challenge, for example with respect to treatment stratification. To further elucidate genomic instability and tumor heterogeneity in older patients, we analyzed the genetic aberration profiles of 39 breast cancer patients aged 50 years and older (median 67 years) with either short (median 2.4 years) or long survival (median 19 years). The analysis was based on copy number enumeration of eight breast cancer-associated genes using multiplex interphase fluorescence in situ hybridization (miFISH) of single cells, and by targeted next-generation sequencing of 563 cancer-related genes. Results: We detected enormous inter- and intratumor heterogeneity, yet maintenance of common cancer gene mutations and breast cancer specific chromosomal gains and losses. The gain of COX2 was most common (72%), followed by MYC (69%); losses were most prevalent for CDH1 (74%) and TP53 (69%). The degree of intratumor heterogeneity did not correlate with disease outcome. Comparing the miFISH results of diploid with aneuploid tumor samples significant differences were found: aneuploid tumors showed significantly higher average signal numbers, copy number alterations (CNAs) and instability indices. Mutations in PIKC3A were mostly restricted to luminal A tumors. Furthermore, a significant co-occurrence of CNAs of DBC2/MYC, HER2/DBC2 and HER2/TP53 and mutual exclusivity of CNAs of HER2 and PIK3CA mutations and CNAs of CCND1 and PIK3CA mutations were revealed. Conclusion: Our results provide a comprehensive picture of genome instability profiles with a large variety of inter- and intratumor heterogeneity in breast cancer patients aged 50 years and older. In most cases, the distribution of chromosomal aneuploidies was consistent with previous results; however, striking exceptions, such as tumors driven by exclusive loss of chromosomes, were identified.

scholarly journals Pathogenesis and Potential Therapeutic Targets for Triple-Negative Breast Cancer

Cancers ◽  
2021 ◽  
Vol 13 (12) ◽  
pp. 2978
Author(s):  
Chia-Jung Li ◽  
Yen-Dun Tony Tzeng ◽  
Yi-Han Chiu ◽  
Hung-Yu Lin ◽  
Ming-Feng Hou ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
High Efficiency ◽  
Early Recurrence ◽  
New Developments ◽  
Great Progress ◽  
Low Toxicity ◽  
Made In

Triple negative breast cancer (TNBC) is a heterogeneous tumor characterized by early recurrence, high invasion, and poor prognosis. Currently, its treatment includes chemotherapy, which shows a suboptimal efficacy. However, with the increasing studies on TNBC subtypes and tumor molecular biology, great progress has been made in targeted therapy for TNBC. The new developments in the treatment of breast cancer include targeted therapy, which has the advantages of accurate positioning, high efficiency, and low toxicity, as compared to surgery, radiotherapy, and chemotherapy. Given its importance as cancer treatment, we review the latest research on the subtypes of TNBC and relevant targeted therapies.

Sign in / Sign up

Export Citation Format

Share Document