Evaluating the effects of RAS and CK2 Inhibitors in ESR1 Mutated Breast Cancer

Background and Hypothesis: Estrogen Receptor alpha (ESR1) is rarely mutated in primary breast cancers but is frequently mutated in metastasis that can appear after many years of anti-estrogen therapy. Mutations to ESR1 can result in estrogen-independent activity of ESR1 causing anti-estrogen to become ineffective. Previous work on this project has led to the hypothesis that RAS pathway activation in metastatic cancer cells as a result of ESR1 mutation leads to elevated CK2 activity which ultimately results in metastatic progression. Therefore, we hypothesize that the use of RAS signaling inhibitors or CK2 inhibitors have efficacy in blocking or reducing the metastatic progression of metastatic breast cancers with hyperactive RAS pathways. Experimental Design or Project Methods: The estrogen receptor positive, anti-estrogen sensitive breast cancer cell line MCF-7 and the same cell line genomically modified to replace wild type ESR1 to breast cancer metastasis enriched Y537S or D538G ESR1 mutation were used in this study. Cells were treated with various concentrations of the RAS pathway inhibitor Salirasib or CK2 inhibitor Silmitasertib and cell proliferation rates were measured using bromodeoxyuridine incorporation ELISA. Results: Thus far, the use of RAS signaling inhibitors or CK2 inhibitors have not shown efficacy in decreasing the proliferation rates of modified ESR1 MCF-7 cells. While there is a general trend of growth inhibition by these inhibitors at a higher concentration, there is no significant difference between the ESR1 mutant expressing cells and their respective controls. Conclusion and Potential Impact: This study will establish the feasibility of using RAS signaling inhibitors or CK2 inhibitors in the treatment of metastatic estrogen receptor-positive breast cancer. Future studies testing the effects of these drugs either alone or in combination with the clinically used anti-estrogen Fulvestrant for not only primary tumor growth but also metastasis in clinically relevant in vivo models may ultimately lead to clinical translation. Finally, demonstrating efficacy in these types of drugs may fuel the further refinement of drugs targeting these pathways to treat metastatic breast cancer.

Liquid biopsy for baseline evaluation of tumor burden in patients with hormone receptor-positive, HER2-negative metastatic breast cancer: A proof of principle study.

e13008 Background: Liquid biopsy-based biomarkers, including circulating tumor DNA (ctDNA), are increasingly important for the characterization of metastatic breast cancer (MBC). Currently, CA15.3 is the most commonly used serum marker for monitoring disease burden. To date, no liquid biopsy-based biomarkers have been proposed for this scope in clinical practice. Methods: The CRO-2018-56 multicenter study prospectively enrolled 83 patients (pts) with luminal-like MBC treated with first line endocrine therapy (ET) and CDK4/6 inhibitors. All pts were characterized for ctDNA through droplet digital PCR (ddPCR) in from 2018 to 2021. Clinicopathological and laboratory characteristics at baseline were tested for associations with tumor markers, ACTB fragments lengths, methylation status of ESR1 main promoters (expressed as promA and promB ratio, i.e., met_ratio) and ESR1/PIK3CA mutational status through Kruskal-Wallis test and Chi-square test. Prognosis was tested in terms of Progression Free Survival (PFS) and Overall Survival (OS) through log-rank test. Results: At baseline, in 26 (31%) pts disease was diagnosed as de novo metastatic, 66 (80%) pts had < 3 of metastatic sites, and 41 (49%) pts had < 5 of metastatic lesions. Bone metastases were detected in 53 (64%) pts, liver metastases in 21 (25%) pts, and lung lesions in 30 (36%) pts. A ctDNA-detected ESR1 mutation and a PIK3CA mutation were found in 15% of pts and in 34% pts, respectively. Met_ratio was > 1.5 in 35 (42%) of pts. Median CA15.3 was 48.2 U/mL and median CEA was 3.8 U/mL. Number of liver metastases and number of metastatic sites were significantly higher in pts with ESR1 mutation (respectively, P = 0.0055 and P = 0.0208). CA15.3 and ctDNA yield were significantly higher in pts with number of metastatic sites ≥ 3, (respectively, P = 0.0164, and P = 0.0239), while number of metastatic sites ≥ 3 and number of metastatic lesions ≥ 5 were significantly associated with CEA > 3.8 U/mL (respectively, P = 0.039, and P = 0.029). Presence of bone metastases was significantly associated with PIK3CA mutation (P = 0.040), while number of metastatic sites ≥ 3 was significantly associated with ESR1 mutation (P = 0.022). No association with tumor burden was observed for different ACTB DNA fragments lengths. Met_ratio > 1.5 was significantly associated with lower number of metastatic lesions (P = 0.031). Number of metastatic sites ≥ 3, high ctDNA yield and CEA were associated with worse OS (respectively P = 0.0465, P = 0.0250 and P = 0.0474), while only CEA impacted on PFS (P = 0.0097). Conclusions: In pts with luminal-like MBC, some liquid biopsy-based biomarkers (i.e., ctDNA-detected ESR1 and PIK3CA mutations, ctDNA yield) were significantly associated with the burden of disease. The potential clinical validity and utility of these results deserve to be tested in an expansion cohort.

Phase I Study of Elacestrant (RAD1901), a Novel Selective Estrogen Receptor Degrader, in ER-Positive, HER2-Negative Advanced Breast Cancer

PURPOSE This phase I study (RAD1901-005; NCT02338349) evaluated elacestrant, an investigational oral selective estrogen receptor degrader (SERD), in heavily pretreated women with estrogen receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer, including those with estrogen receptor gene alpha ( ESR1) mutation. The primary objective was to determine the maximum tolerated dose and/or recommended phase II dose (RP2D). METHODS The study consisted of a 3 + 3 design (elacestrant capsules) followed by expansion at RP2D (400-mg capsules, then 400-mg tablets) for the evaluation of safety and antitumor activity. Elacestrant was taken once daily until progression or intolerability. RESULTS Of 57 postmenopausal women enrolled, 50 received RP2D (400 mg once daily): median age, 63 years; median three prior anticancer therapies, including cyclin-dependent kinase 4,6 inhibitors (CDK4/6i; 52%), SERD (52%), and ESR1 mutation (circulating tumor DNA; 50%). No dose-limiting toxicities occurred; the most common adverse events at RP2D (400-mg tablet; n = 24) were nausea (33.3%) and increased blood triglycerides and decreased blood phosphorus (25.0% each). Most adverse events were grade 1-2 in severity. The objective response rate was 19.4% (n = 31 evaluable patients receiving RP2D), 15.0% in patients with prior SERD, 16.7% in patients with prior CDK4/6i, and 33.3% in patients with ESR1 mutation (n = 5/15). The clinical benefit rate (24-week) was 42.6% overall (n = 47 patients receiving RP2D), 56.5% (n = 23, ESR1 mutation), and 30.4% (n = 23, prior CDK4/6i). Elacestrant clinical benefit was associated with decline in ESR1 mutant allele fraction. CONCLUSION Elacestrant 400 mg orally once daily has an acceptable safety profile and demonstrated single-agent activity with confirmed partial responses in heavily pretreated patients with estrogen receptor–positive metastatic breast cancer. Notably, responses were observed in patients with ESR1 mutation as well as those with prior CDK4/6i and prior SERD. A phase III trial investigating elacestrant versus standard endocrine therapy is ongoing.

ESR1 mutation as potential predictive marker for choice of treatment tactics in hormone-resistant HR+/HER2-negative breast cancer

The analysis of the current strategy for the treatment of advanced HR+/HER2-negative metastatic breast cancer (mBC) was carried out, the criteria for hormone sensitivity and hormone resistance were given, and the changes in the classification of tumors were reflected taking into account the level of expression of estrogen receptors. A detailed characterization of a new potential marker of acquired hormone resistance - activating somatic mutation of the estrogen receptor gene ESR1, leading to constitutive ligand-independent activity of the estrogen receptor is given; describes the predictive and prognostic role of ESR1 mutation, its association with the clinical course of the disease and response to endocrine therapy. The paper presents studies to find the optimal treatment regimen after progression to CDK4/6 inhibitors, including the emergence of ESR1 mutations. The characteristics and key advantages of eribulin chemotherapy in patients with hormone-resistant mBC are presented, and preliminary results of the EMPOWER study on the potential for eribulin use after progression to CDK4/6 inhibitors are presented. This review will help form the concept of a personalized approach to the choice of a treatment strategy for hormone-resistant mBC.

Was ist neu bei der Diagnostik und Therapie des Mammakarzinoms? – Aktuelle Standards in der Behandlung von Brustkrebs

Was ist neu? Vorsorge, Früherkennung und familiärer Brustkrebs Mit dem Mammografie-Screening für Frauen ab dem 50. Lebensjahr steht in Deutschland eine etablierte Früherkennungsmaßnahme zur Verfügung. Eine Reduktion der Mortalität ist gesichert. Das Screening kann mittlerweile auch bei Frauen über 70 fortgeführt werden. Durch intensive Forschung im Bereich des familiären Mammakarzinoms kann das Hochrisikopatientenkollektiv präziser bestimmt und einer intensivierten Früherkennung zugeführt werden. Therapie lokal begrenzter Stadien – Senkung der Radikalität Die Behandlung erfolgt zielgerichtet und so wenig radikal wie möglich. Nach neoadjuvanter Chemotherapie kann immer öfter auf eine Brustamputation verzichtet werden. Die axilläre Lymphknotendissektion (ALND) bleibt wenigen Fällen vorbehalten. Die molekulare Subtypisierung ermöglicht individualisierte medikamentöse Therapien in der kurativen Absicht. Rekonstruktive Chirurgie Das BIA-ALCL stellt eine seltene Brustimplantat-assoziierte Erkrankung dar, bei der in den meisten Fällen eine Heilung möglich ist. Trotz steigender Inzidenz ist von Implantateinlagen nach adäquater Aufklärung der Patientin in Deutschland nicht abzuraten. Therapie des metastasierten Karzinoms Zur Behandlung des metastasierten Mammakarzinoms sollte wenn möglich eine gut verträgliche Therapie zur Erhaltung der Lebensqualität gewählt werden. Auch hier stehen immer mehr individualisierte Optionen zur Verfügung. Nachsorge Der Zeitraum der Nachsorge weitet sich aufgrund der Tumorbiologie auf 10 Jahre aus. Ausblick Eine ESR1-Mutation kann zukünftig möglicherweise als prädiktiver Marker hinsichtlich einer antihormonellen Therapie in der Metastasierung genutzt werden. Für eine PD-1-Blockade gibt es vielversprechende Ergebnisse in der neoadjuvanten Behandlung des triple-negativen Mammakarzinoms (TNBC).