Abstract PD8-07: Identifying steroid hormone receptor gene mutations in patients with newly diagnosed estrogen receptor positive metastatic breast cancer

Author(s):  
AM Fowler ◽  
S Rassman ◽  
M DeGrave ◽  
I Ong ◽  
GL Powers ◽  
...  
Nature ◽  
1984 ◽  
Vol 312 (5996) ◽  
pp. 779-781 ◽  
Author(s):  
Roger Miesfeld ◽  
Sam Okret ◽  
Ann-Charlotte Wikström ◽  
Örjan Wrange ◽  
Jan-Åke Gustafsson ◽  
...  

2016 ◽  
Vol 34 (25) ◽  
pp. 2961-2968 ◽  
Author(s):  
Charlotte Fribbens ◽  
Ben O’Leary ◽  
Lucy Kilburn ◽  
Sarah Hrebien ◽  
Isaac Garcia-Murillas ◽  
...  

Purpose ESR1 mutations are selected by prior aromatase inhibitor (AI) therapy in advanced breast cancer. We assessed the impact of ESR1 mutations on sensitivity to standard therapies in two phase III randomized trials that represent the development of the current standard therapy for estrogen receptor–positive advanced breast cancer. Materials and Methods In a prospective-retrospective analysis, we assessed ESR1 mutations in available archived baseline plasma from the SoFEA (Study of Faslodex Versus Exemestane With or Without Arimidex) trial, which compared exemestane with fulvestrant-containing regimens in patients with prior sensitivity to nonsteroidal AI and in baseline plasma from the PALOMA3 (Palbociclib Combined With Fulvestrant in Hormone Receptor–Positive HER2-Negative Metastatic Breast Cancer After Endocrine Failure) trial, which compared fulvestrant plus placebo with fulvestrant plus palbociclib in patients with progression after receiving prior endocrine therapy. ESR1 mutations were analyzed by multiplex digital polymerase chain reaction. Results In SoFEA, ESR1 mutations were found in 39.1% of patients (63 of 161), of whom 49.1% (27 of 55) were polyclonal, with rates of mutation detection unaffected by delays in processing of archival plasma. Patients with ESR1 mutations had improved progression-free survival (PFS) after taking fulvestrant (n = 45) compared with exemestane (n = 18; hazard ratio [HR], 0.52; 95% CI, 0.30 to 0.92; P = .02), whereas patients with wild-type ESR1 had similar PFS after receiving either treatment (HR, 1.07; 95% CI, 0.68 to 1.67; P = .77). In PALOMA3, ESR1 mutations were found in the plasma of 25.3% of patients (91 of 360), of whom 28.6% (26 of 91) were polyclonal, with mutations associated with acquired resistance to prior AI. Fulvestrant plus palbociclib improved PFS compared with fulvestrant plus placebo in both ESR1 mutant (HR, 0.43; 95% CI, 0.25 to 0.74; P = .002) and ESR1 wild-type patients (HR, 0.49; 95% CI, 0.35 to 0.70; P < .001). Conclusion ESR1 mutation analysis in plasma after progression after prior AI therapy may help direct choice of further endocrine-based therapy. Additional confirmatory studies are required.


2020 ◽  
Vol 18 (7.5) ◽  
pp. 941-944
Author(s):  
William J. Gradishar

Systemic treatment for metastatic breast cancer now incorporates many targeted agents and a plethora of combinations specific to the breast cancer subtype. New to the treatment paradigm are fam-trastuzumab deruxtecan-nxki, and tucatinib for HER2-positive disease; the PI3K inhibitor alpelisib in combination with fulvestrant for estrogen receptor–positive and PIK3CA-mutated tumors; PARP inhibitors for patients with germline BRCA1/2 mutations; and the anti–PD-L1 agent atezolizumab in combination with albumin-bound paclitaxel for triple-negative disease with PD-L1 mutations in tumors. In addition, for estrogen receptor–positive disease, the role of CDK4/6 inhibitors increased substantially during the past year, as overall survival results have emerged. These targeted agents are greatly improving patient outcomes, and thus have all been incorporated into the NCCN Guidelines for Breast Cancer.


2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 1049-1049
Author(s):  
Alberto A. Gabizon ◽  
Nathan Cherny ◽  
Rut Isacson ◽  
Areen Abu Remilah ◽  
Alberto Gabizon ◽  
...  

1049 Background: This is a single center phase 1b study of a regimen of pembrolizumab (PBZ) and pegylated liposomal doxorubicin (PLD) in endocrine-resistant breast cancer. PLD was chosen as chemotherapy component because it is mildly myelosuppressive and non-immunosuppressive and contains doxorubicin, a strong immunogenic cell death inducer. Methods: Patients with estrogen receptor positive, HER2 negative, metastatic breast cancer, whose disease progressed on hormonal and biological therapy and up to 2 chemotherapy lines were eligible for enrollment. PLD, 30 mg/m2, and PBZ, 200 mg flat dose, were infused on day 1 of every 3-week cycles. The main study objectives were safe dose clearance, characterization of dose-limiting toxicities (DLT), tumor response, and pharmacokinetic analysis of PLD and PBZ during the first 3 cycles of treatment in a 1st cohort of 6 patients and a 2nd confirmatory cohort of 6-9 patients. Patients with partial response (PR) or stable disease (SD) continued on the extended phase of the study consisting of 9 additional cycles during which further safety information was collected. All patients were followed-up for survival. Results: 12 patients were recruited (median age 61 y, range 45-91). 9 patients had received prior doxorubicin treatment. 82 treatments have been administered (median: 7, range 2-13). Overall, treatment was well tolerated. DLT including infusion reactions, grade ≥2 myelosuppression, hair loss and mucocutaneous toxicity were not observed in the first 3 cycles. Subsequently, skin toxicity (grade 2-3 palmar-plantar erythema) was observed forcing treatment delays of 1-2 weeks. Except for 2 cases of subclinical hypothyroidism, there were no other apparent PBZ-related side-effects. There was no evidence of cardiac toxicity. There were 2 early deaths (days 25 and 45) probably related to disease progression. Upon reevaluation on week 9, we observed: 2 patients with PD, 4 with SD, 2 with PR (15+ and 5+ mth), 1 with no measurable disease, and 1 early to evaluate. Three out of 5 patients responded well to post-study chemotherapy with durable improvement or stabilization (range, 5 to 11+ mth). Median follow-up is 14 mth. Median survival has not been reached with 4 deaths and a longest survivor of 19+ mth. Median progression-free survival is 6.0 mth. The clearance of PLD was slow with high Cmax, long T½ and small Vd. There was a significant increase in the AUC of PLD between the 1st and 3rd cycle (median: 2,649 vs 3,422 mg*h/l, p = 0.039). Analysis of PBZ plasma levels is ongoing. Conclusions: The combination of PLD and PBZ is well tolerated and feasible for extended treatment. Dose interval of PLD should be lengthened to 4 weeks after 2-3 cycles to prevent skin toxicity. The late appearance of skin toxicity is probably related to a delay in PLD clearance after 2 treatment cycles with PLD and PBZ. Clinical trial information: NCT03591276 .


Cancers ◽  
2019 ◽  
Vol 11 (5) ◽  
pp. 684 ◽  
Author(s):  
Nadiia Lypova ◽  
Lilibeth Lanceta ◽  
Alana Gipson ◽  
Stephanie Vega ◽  
Rodolfo Garza-Morales ◽  
...  

While clinical responses to palbociclib have been promising, metastatic breast cancer remains incurable due to the development of resistance. We generated estrogen receptor-positive (ER+) and ER-negative (ER−) cell line models and determined their permissiveness and cellular responses to an oncolytic adenovirus (OAd) known as Ad5/3-delta24. Analysis of ER+ and ER− palbociclib-resistant cells revealed two clearly distinguishable responses to the OAd. While ER+ palbociclib-resistant cells displayed a hypersensitive phenotype to the effects of the OAd, ER− palbociclib-resistant cells showed a resistant phenotype to the OAd. Hypersensitivity to the OAd in ER+ palbociclib-resistant cells correlated with a decrease in type I interferon (IFN) signaling, an increase in viral entry receptor expression, and an increase in cyclin E expression. OAd resistance in ER− palbociclib-resistant cells correlated with an increase in type I IFN signaling and a marked decrease in viral entry receptor. Using the OAd as monotherapy caused significant cytotoxicity to both ER+ and ER− palbociclib-sensitive cell lines. However, the addition of palbociclib increased the oncolytic activity of the OAd only in ER+ palbociclib-sensitive cells. Our studies provide a mechanistic base for a novel anti-cancer regimen composed of an OAd in combination with palbociclib for the treatment of ER+ breast cancer.


2020 ◽  
Vol 11 (2) ◽  
pp. 63-75 ◽  
Author(s):  
Amy M. Fowler ◽  
Kelley Salem ◽  
Michael DeGrave ◽  
Irene M. Ong ◽  
Shane Rassman ◽  
...  

1997 ◽  
Vol 15 (7) ◽  
pp. 2494-2501 ◽  
Author(s):  
C A Russell ◽  
S J Green ◽  
J O'Sullivan ◽  
H E Hynes ◽  
G T Budd ◽  
...  

PURPOSE A phase III randomized trial was performed to determine whether combination hormonal therapy with aminoglutethimide (AG) and hydrocortisone (HC) plus megestrol acetate (MA) improved response rates, response duration, or increased survival over the sequential use of each hormone in women with estrogen receptor-positive metastatic breast cancer (MBC) who had maintained stable disease for at least 6 months or responded to tamoxifen. PATIENTS AND METHODS Two hundred eighty-eight postmenopausal women with progressive estrogen receptor-positive MBC were randomly selected to receive MA 40 mg four times daily (arm I), AG 250 mg four times daily with HC 40 mg daily in divided doses (arm II), versus the combination of MA plus AG given at the same dosages (arm III). Patients on arms I and II who progressed after an adequate trial were crossed over to the other treatment arm. RESULTS Two hundred thirty-five eligible patients were evaluated for response, time to treatment failure, and survival. Response was only reported for patients with measurable disease and was not statistically different among the three arms. There were two partial responses (PRs) on MA (6%), four complete responses (CRs) and six PRs on AG (24%), and eight PRs and three CRs on MA plus AG (23%) in 32, 42, and 48 measurable patients, respectively. Median times to treatment failure were also similar at 5, 4, and 7 months. Survival was also not statistically different among the three arms at 26, 27, and 26 months for arms I, II, and III, respectively. Toxicity was greater in the two AG arms with respect to fatigue, nausea and vomiting, and rash. CONCLUSION With the exception of toxicity, there is no response, time to treatment failure, or survival benefit for any one group when comparing MA, AG, or the combination at their stated doses in women with estrogen receptor-positive MBC who had previously responded to or stabilized with tamoxifen.


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