Abstract GS4-05: Neoadjuvant chemotherapy (NCT) response in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC) resistant to endocrine therapy (ET) in the ALTERNATE trial (Alliance A011106)

2021 ◽  
Author(s):  
Cynthia X Ma ◽  
Vera Suman ◽  
A. Marilyn Leitch ◽  
Souzan Sanati ◽  
Kiran Vij ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Neoadjuvant Chemotherapy ◽  
Postmenopausal Women ◽  
Endocrine Therapy ◽  
Clinical Stage ◽  
Stage Ii ◽  
Her2 Breast Cancer ◽  
Estrogen Receptor Positive

scholarly journals NEOADJUVANT ENDOCRINE THERAPY FOR PATIENTS WITH ESTROGEN-RECEPTOR-POSITIVE BREAST CANCER

2018 ◽  
Vol 17 (3) ◽  
pp. 11-19
Author(s):  
V. F. Semiglazov ◽  
V. V. Semiglazov ◽  
G. A. Dashyan ◽  
P. V. Krivorotko ◽  
V. G. Ivanov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Neoadjuvant Chemotherapy ◽  
Endocrine Therapy ◽  
Locally Advanced ◽  
Response To Therapy ◽  
Neoadjuvant Endocrine Therapy ◽  
Receive Hormone Therapy ◽  
Study Results ◽  
Estrogen Receptor Positive

More than 70 % of patients with breast cancer have estrogen-receptor-positive tumors (ER+) and are considered hormone- sensitive. That is why a vast majority of patients with early operable  tumors receive adjuvant endocrine therapy. Patients with metastatic  ER+ breast cancer also receive hormone therapy as first-line  treatment. Patients with ER+/PR+ locally advanced breast cancer  including potentially operable cases (cT2N1, cT3N0M0) are still a  subject to neoadjuvant chemotherapy in most of the oncology  centers in Russia and worldwide. More than 10 years ago, several  trials evaluating the efficacy of neoadjuvant endocrine therapy were  conducted in the Petrov Research Institute of Oncology (aromatase  inhibitors vs tamoxifen, neoadjuvant endocrine therapy vs  neoadjuvant chemotherapy, etc.) The primary endpoint was the  evaluation of pathologic complete/partial response to therapy and  the frequency of breast-conserving surgeries following neoadjuvant  treatment. We now represent 10-year long-term follow-up data on  comparison of neoadjuvant chemotherapy with neoadjuvant  endocrine therapy after retrospective determination of IHC- phenotypes of 239 patients with ER+ breast cancer. The study  results show tendency to better 10-year disease-free survival in  patients with luminal-A breast cancer who received endocrine  therapy compared to neoadjuvant chemotherapy (72.8 % vs 53.9  %, respectively, p=0.062) There were no statistically significant  differences in DFS rates among patients with the luminal B breast  cancer subtype (41 % vs 40 %) The discovery of biomarkers of  potential resistance to endocrine therapy (cycline-dependant kinase  activity [cdk 4/6], estrogenreceptor mutation [ESR1], mTOR  signaling pathway activity, co-expression of the ER and HER2neu  [ER+/ HER2neu3+]) and ways to inhibit the activity of the resistance pathways (palbocyclib, everolimus, etc.) have expanded the  armamentarium of endocrine-therapy for not only metastatic and  locally-advanced but also operable cases of ER+ breast cancer.

Combination mTORC1/2 and BCL- XL inhibition in endocrine and CDK4/6-resistant estrogen receptor-positive breast cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14653-e14653
Author(s):  
Sarah Sammons ◽  
Grace Anderson ◽  
Suzanne Wardell ◽  
Donald P. McDonnell ◽  
Paul Kelly Marcom ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Endocrine Therapy ◽  
Large Animal ◽  
Cancer Resistance ◽  
Initial Development ◽  
Large Animal Models ◽  
Her2 Breast Cancer ◽  
Estrogen Receptor Positive

e14653 Background: Endocrine therapy plus CDK 4/6 inhibition has led to impressive improvements in progression-free survival in patients with advanced, estrogen receptor positive (ER+)/HER2-negative (HER2-) breast cancer. Resistance inevitably emerges, leaving patients with few proven therapeutic options. Our group has recently found that treatment of PIK3CA mutant ER+/HER2- breast cancer with inhibitors of mTORC1/2 and BCL-XL causes impressive synergistic growth suppression and apoptosis induction compared to either agent alone in vitro and in vivo. We sought to assess activity in clinically relevant models of PIK3CA mutant ER+ breast cancer with acquired resistance to endocrine therapy and CDK4/6 inhibition. Methods: Using orthotopic MCF-7 xenograft tumors (ER+/ PIK3CA mutant) that were evolved through serial passaging in vivo to develop tamoxifen resistance (TamR), we developed models of resistant disease. TamR xenograft- bearing mice were then treated for 4-6 weeks with palbociclib (50 mg/kg qd), fulvestrant (100mg/kg qw), or the combination. Mice in each treatment group were divided into two groups following the initial development of resistance, defined by steady growth for 1-2 weeks: one receiving vehicle and the other receiving low dose MLN0128 0.3 mg/kg qd (mTORC1/2 inhibitor) + ABT-737 25 mg/kg qd (BCL-XL /BCL-2 inhibitor). Results: Combination BCL-XL (ABT-737) + mTORC1/2 (MLN0128) inhibition significantly inhibited growth in tamoxifen (p = 0.0045), fulvestrant/tamoxifen (p = 0.0035), palbociclib/tamoxifen (p = 0.0155), and palbociclib/tamoxifen/fulvestrant (0.005) resistant tumors compared to controls. These results were observed without significant animal toxicity, dose-limiting thrombocytopenia secondary to BCL-XL inhibition, or toxicity to normal breast epithelial cells. We have observed tumor regressions in multiple models using doses five- to 12-fold lower than the equivalent doses required to cause clinically meaningful thrombocytopenia in humans and large animal models. Conclusions: Our data establish the rationale for investigating the combination of BCL-XL and mTORC1/2 inhibition in a clinical trial of advanced PIK3CA mutant, ER+/HER2- breast cancer after progression on CDK 4/6 and endocrine therapy. Preclinical work is ongoing with novel inhibitors of BCL-XL.

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