Elacestrant May Improve Outcomes for Patients Whose Metastatic Breast Cancers Progressed on Prior Endocrine Therapy
Elacestrant is the first oral selective estrogen receptor degrader to show clinical benefit over standard of care in a phase III clinical trial for this patient population

The investigational oral selective estrogen receptor degrader (SERD) elacestrant significantly decreased the risk of death or disease progression and increased progression-free survival compared with standard-of-care endocrine therapy for postmenopausal patients with estrogen receptor (ER)-positive/HER2-negative metastatic breast cancers that progressed on prior endocrine and targeted therapies, according to results from the phase III EMERALD trial, which were presented during Wednesday’s General Session.

“There is an urgent unmet need for alternative SERDs that are effective against ER-positive metastatic breast cancer, including those with ESR1 mutations,” said Aditya Bardia, MD, MPH, Director of the Breast Cancer Research Program at Mass General Cancer Center, and Associate Professor at Harvard Medical School.

To understand how elacestrant compares to the current standard of care, Dr. Bardia and colleagues initiated the phase III EMERALD trial, making elacestrant the first oral SERD to be studied in a randomized phase III clinical trial.

“Elacestrant is the first oral SERD to demonstrate a statistically significant and clinically meaningful improvement of progression-free survival in patients with ER-positive/HER2-negative metastatic breast cancer in the second- and third-line settings, including for patients whose tumors harbor ESR1 mutations,” said Dr. Bardia. “Elacestrant was well tolerated with manageable and reversible side effects. This therapy has the potential to become the new standard of care for patients with this cancer.”

Abstract: GS2-02 Elacestrant, an oral selective estrogen receptor degrader (SERD), vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: Results of EMERALD phase 3 trial

Click here to read the full press release from the American Association for Cancer Research (AACR).

Tamoxifen May Boost PI3K Signaling to Increase Uterine Cancer Risk in Patients With Breast Cancer
Concurrent treatment with PI3K pathway inhibitors may benefit at-risk patients

Uterine cancers that developed in patients treated with tamoxifen had fewer PI3K pathway mutations and may have instead been driven by tamoxifen-induced PI3K pathway activation, according to results presented at SABCS during Wednesday’s General Session.

In preclinical studies, the increase in PI3K pathway activation was mitigated by treatment with the PI3K inhibitor alpelisib.

“The model for how secondary cancers occur after chemotherapy, for example, is that cells acquire driver mutations that lead to clonal outgrowth,” said presenter Kirsten Kübler, MD, PhD, Associate Scientist at the Broad Institute of MIT and Harvard, who recently joined the faculty of the Berlin Institute of Health at Charité in Berlin. “Our results extend that view in the sense that a drug could directly activate a signaling pathway instead of creating mutations that activate the pathway.”

To investigate the mechanisms of decreased PI3K pathway mutations in TA-UCs, the researchers examined uterine tissue from tamoxifen-treated mice. They found that tamoxifen increased the expression of Ki67, a marker of cell proliferation. They also sequenced RNA from the uterine tissue and stained for phosphorylated proteins in the PI3K pathway—such as IGF1R, AKT, and S6—which indicates pathway activation. These data revealed a significant increase in PI3K pathway activation among tamoxifen-treated mice.

Dr. Kübler suggested that the tamoxifen-driven increase in PI3K pathway signaling may, in effect, substitute for a PIK3CA or PIK3R1mutation to stimulate uterine cancer development.

“What’s unique is that we found a new mechanistic explanationforthe development of therapy-related tumorsthat,to our knowledge,has not been described previously,” Dr. Kübler said.

Abstract: GS2-09 Tamoxifen instigates uterine cancer development by activating PI3K signaling and supersedes PIK3CA driver mutations

Click here to read the full press release from the American Association for Cancer Research (AACR).

The following abstracts were also presented during Wednesday’s General Session. These presentations will be available to registered SABCS participants for on-demand viewing until March 10, 2022. Click here to find these and other abstracts presented this week at SABCS 2021.

GS2-00 Correlative analysis of overall survival by intrinsic subtype across the MONALEESA-2, -3, and -7 studies of ribociclib + endocrine therapy in patients with HR+/HER2− advanced breast cancer

GS2-01 Overall survival subgroup analysis by metastatic site from the phase 3 MONALEESA-2 study of first-line ribociclib + letrozole in postmenopausal patients with advanced HR+/HER2− breast cancer

GS2-04 Aromatase inhibitors versus tamoxifen in pre-menopausal women with estrogen receptor positive early stage breast cancer treated with ovarian suppression: A patient level meta-analysis of 7,030 women in four randomised trials

GS2-05 Randomized comparison of adjuvant aromatase inhibitor exemestane (E) plus ovarian function suppression (OFS) vs tamoxifen (T) plus OFS in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): update of the combined TEXT and SOFT trials

GS2-06 Taxane with anthracycline versus taxane without anthracycline: An individual patient-level meta-analysis of 16,500 women with early-stage breast cancer in 13 randomised trials

GS2-07 Updated results from a phase 3 randomized clinical trial in participants (pts) with 1-3 positive lymph nodes (LN), hormone receptor-positive (HR+) and HER2-negative (HER2-) breast cancer (BC) with recurrence score (RS) < 25 randomized to endocrine therapy (ET) +/- chemotherapy (CT): SWOG S1007 (RxPONDER)

GS2-10 Nimbus: A phase 2 trial of nivolumab plus ipilimumab for patients with hypermutated her2-negative metastatic breast cancer (MBC)