Publication

Article

Oncology Live®
Vol. 23/No. 5
Volume 23
Issue 05

ESR1 Data Fuel Novel Breast Cancer Strategies

Mutations on the ESR1 gene, which encodes the estrogen receptor, have emerged as an important driver of resistance to endocrine therapies, which form the backbone of treatment for patients with ER-positive, HER2-negative breast cancer.

Breast Cancer

Breast Cancer

Mutations on the ESR1 gene, which encodes the estrogen receptor (ER), have emerged as an important driver of resistance to endocrine therapies, which form the backbone of treatment for patients with ER-positive, HER2-negative breast cancer.1,2

Patients with these mutations, which arise largely in response to the selective pressure of aromatase inhibitor (AI) therapy, have a poorer prognosis.3-5 As investigators have uncovered more details of the role of ESR1 mutations in resistance, novel treatment strategies that could improve patient outcomes have begun to emerge.4,5

Studies have suggested that monitoring the emergence of ESR1 mutations in the blood could help guide treatment decisions, but demonstration of clinical utility has remained elusive.3,6 The PADA-1 trial (NCT03079011), results from which were presented at the 2021 San Antonio Breast Cancer Symposium (2021 SABCS), was the first to demonstrate that ESR1 mutations can be detected before tumor progression and can be effectively targeted by switching from an AI to fulvestrant (Faslodex), a selective estrogen receptor downregulator (SERD).7

Investigators are also pursuing next-generation endocrine therapies that they hope will have more efficacy against ESR1-mutant tumors; such agents could complement AIs or fulvestrant as the standard of care if efficacy is established.

Among these newer agents are oral SERDs, such as elacestrant (RAD-1901), which is under investigation in the phase 3 EMERALD trial (NCT03778931). Data presented at 2021 SABCS suggest that although elacestrant is effective in the study population as a whole, its effects are most significant in patients with ESR1 mutations.

Novel selective estrogen receptor modulators (SERMs)—the drug class of tamoxifen, the first endocrine therapy approved for the treatment of breast cancer9—have also demonstrated antitumor activity in ESR1-mutant breast cancer.5 Among the forerunners, lasofoxifene is now in phase 2 testing, including in a head-to-head comparison with fulvestrant in patients with ESR1 mutations in the ELAINE trial (NCT03781063). The study is fully enrolled and expected to report top-line data later this year.10

ESR1 Mutations and AIs

Endocrine therapies comprise several distinct classes of drugs that are designed to either inhibit the production of estrogen with AIs such as letrozole, anastrozole, and exemestane or block its effects on the ER, with therapies such as SERMs (eg, tamoxifen) and SERDs (eg, fulvestrant).11

Endocrine therapies have now been incorporated into the neoadjuvant, adjuvant, and metastatic settings for the treatment of patients with ER-positive, HER2-negative disease.11 Although most patients initially derive benef it from these drugs, resistance presents a major challenge to their efficacy. Seeking to improve patient outcomes, investigators have long sought a better understanding of the mechanisms underlying this resistance.2

Research in this field has already led to significant gains in patient outcomes as combination therapies have been introduced. Endocrine therapies have been successfully combined with targeted therapies, including CDK4/6 inhibitors and PI3K inhibitors, drugs that target pathways implicated in endocrine resistance.12

The discovery that activating mutations in ESR1, the gene encoding the ER, are enriched in patients with metastatic ER-positive breast cancer has led to a growing appreciation of the importance of these mutations as a key mechanism of resistance.3,5,13 Studies examining metastatic ER-positive breast cancer have revealed that ESR1 mutations occur in less than 1% of patients who are endocrine therapy naïve, but the prevalence is as great as 40% among those treated with endocrine therapy. ESR1 mutations are also found in patients treated with neoadjuvant and adjuvant endocrine therapy, but at approximately 2% to 7%, the incidence is significantly lower than in the metastatic setting.3,5,13

ESR1 mutations may have important implications for the selection of endocrine therapy for metastatic breast cancer because studies suggest that these alterations are predominantly acquired after treatment with AIs. Although preclinical studies suggest that ESR1 mutations significantly reduce the ER-binding affinity of both fulvestrant and tamoxifen, retrospective analyses of clinical trials found that ESR1 mutations were not enriched following treatment with either of these drugs.3,5,13

However, the evolution of these mutations may be more nuanced than that. Findings from an analysis of the phase 3 PALOMA-3 trial (NCT01942135), in which patients who had progressed on endocrine therapy were randomized to fulvestrant or fulvestrant plus the CDK4/6 inhibitor palbociclib (Ibrance), found that although overall ESR1 mutations were not enriched following fulvestrant treatment, the Y537S mutation was selectively enriched. This result suggests that ESR1 Y537S specifically drives resistance to fulvestrant.14

A Predictive Biomarker?

In retrospective analyses, ESR1 mutations have been shown to be associated with poorer outcomes in patients treated with AIs. In the AI arms of the SoFEA (NCT00253422) and EFECT (NCT00065325) trials, which evaluated the efficacy of fulvestrant compared with exemestane after progression on a nonsteroidal AI, patients with ESR1 mutations had significantly shorter median progression-free survival (PFS) and lower rates of 1-year overall survival (OS) compared with patients with wild-type ESR1.15,16

Although ESR1 mutations are clearly an important mechanism of resistance to AI monotherapy, single-agent endocrine therapies are not among the preferred regimens for second and subsequent lines of therapy in the current treatment paradigm, according to National Comprehensive Cancer Network guidelines. Instead, they are frequently used in combination regimens with CDK4/6 inhibitors (palbociclib, abemaciclib [Verzenio], or ribociclib [Kisqali]), the mTOR inhibitor everolimus (Afinitor), or the PI3K inhibitor alpelisib (Piqray) in patients with PIK3CA mutations.17

Analyses of data from clinical trials have revealed that ESR1 mutations predict poorer outcomes for patients treated with an AI in combination with palbociclib or ribociclib, but not for patients treated with fulvestrant in combination with these CDK4/6 inhibitors; this mirrors findings for AI and fulvestrant as monotherapies. Perhaps because it is the only CDK4/6 inhibitor with singleagent activity, abemaciclib (either as monotherapy or, notably, combined with an AI) does not show reduced efficacy in patients with ESR1 mutations.5

In the BOLERO-2 trial (NCT00863655), although there was a median PFS benefit from the addition of everolimus to exemestane irrespective of patients’ ESR1 status, ESR1 mutations were associated with shorter median OS.18 Meanwhile, in a phase 1/2 trial (NCT01870505) evaluating the combination of alpelisib and an AI, ESR1 mutations were significantly associated with a lack of clinical benefit.19

The ongoing phase 2 BYLieve trial (NCT03056755) is evaluating alpelisib combined with fulvestrant (cohort A) or letrozole (cohort B) in patients with PIK3CA-mutated ER-positive, HER2-negative advanced breast cancer after progression on a CDK4/6 inhibitor plus an AI or fulvestrant.

At 2021 SABCS, results of an analysis of the impact of ESR1 mutations on efficacy in both cohorts were presented. In the fulvestrant plus alpelisib cohort, there was no significant difference in median PFS between patients with and without ESR1 mutations (5.55 months vs 8.28 months; HR, 0.76; 95% CI, 0.44-1.33; P = .3). In the letrozole plus alpelisib cohort, however, median PFS was significantly reduced in patients with ESR1 mutations (4.57 months vs 7.03 months; HR, 0.55; 95% CI, 0.32-0.92; P = .02).20

Watch and Switch Approach

Studies show that the development of acquired ESR1 mutations occurs prior to clinical progression in patients treated with AIs; thus, serial monitoring of ESR1 mutations during treatment could facilitate therapeutic decision-making at a critical time.21

Circulating tumor DNA (ctDNA), extracted from blood plasma, can be used to detect ESR1 mutations in patients with metastatic ER-positive breast cancer. This has demonstrated excellent sensitivity and concordance with mutation status according to tumor tissue biopsy.22-24

The clinical utility of ESR1 mutations in guiding management decisions is an open question, and the ongoing phase 3 PADA-1 study is the first prospective clinical trial specifically seeking to provide an answer. Patients with previously untreated ER-positive, HER2-negative metastatic breast cancer received a combination of an AI and palbociclib as frontline therapy and underwent ctDNA ESR1 mutation testing every 2 months7 in the first part of this trial. In the second part of the trial, patients with ctDNA evidence of ESR1 mutation emergence were randomized to either continue with the same treatment regimen or switch to a combination of fulvestrant and palbociclib.

Data from part 1 were presented at a conference in 2020. Of the 1017 patients evaluated, 3.2% had an ESR1 mutation at baseline, and these patients had a worse prognosis (median PFS, 11.0 months vs 26.7 months; HR, 2.3; P < .001). Patients treated with an AI as adjuvant therapy were more likely to have an ESR1 mutation (P < .01). In 69% of the patients with a baseline ESR1 alteration, the mutation was cleared after 4 weeks of treatment; these patients experienced improved median PFS compared with those without mutation clearance (24.1 months vs 7.4 months, respectively).25,26

A total of 172 patients were randomized in part 2 of PADA-1. After a median follow-up of 26 months, median PFS was significantly prolonged by switching from the AI to fulvestrant upon ctDNA detection of emerging ESR1 mutation (11.9 months for patients who switched vs 5.7 months for those who did not; HR, 0.63; 95% CI, 0.45-0.88; P = .007).7

Several clinical trials are now evaluating this “watch and switch” strategy in the frontline setting in metastatic breast cancer. These include the phase 3 SERENA-6 trial (NCT04964934), which is testing the switch to a novel oral SERD, camizestrant (AZD9833), from an AI following detection of ESR1 mutations.

Novel Treatment Strategies

A significant focus of ongoing clinical research is the pursuit of more effective treatment strategies for ESR1-mutant disease.

Numerous drugs are being developed, including novel SERMs such as lasofoxifene; orally bioavailable SERDs (fulvestrant is administered intramuscularly), such as elacestrant and amcenestrant (SAR439859); a SERM/SERD hybrid, bazedoxifene (Duavee); and the first-in-class selective ER covalent antagonist H3B-6545.5,27

These agents have been shown to retain efficacy in the presence of ESR1 mutations and in models of endocrine resistance in preclinical studies.5 Preliminary clinical trial data have recently emerged for several of these drugs.

In the phase 1/2 AMEERA-1 trial (NCT03284957), patients with ER-positive, HER2-negative metastatic breast cancer who had previously received endocrine therapy were treated with amcenestrant, either as monotherapy or in combination with palbociclib. Both amcenestrant regimens demonstrated promising antitumor activity, regardless of patients’ ESR1 mutation status.28,29

Results from the phase 1 EMBER trial (NCT04188548) suggested clinical benefit of monotherapy with another oral SERD, imlunestrant (LY3484356), irrespective of ESR1 mutation status, in patients with heavily pretreated ER-positive, HER2-negative metastatic breast cancer.30

These drugs and others are being evaluated in ongoing phase 3 clinical trials that are assessing the impact of ESR1 mutations on patient outcomes. A presentation at 2021 SABCS described results from the phase 3 EMERALD trial comparing elacestrant to endocrine therapy (fulvestrant or an AI) in patients with ER-positive, HER2-negative metastatic breast cancer previously treated with 1 or 2 lines of endocrine therapy, including in combination with a CDK4/6 inhibitor.

Of the 477 patients who were randomized, 228 had ESR1 mutations. In the overall population, elacestrant reduced the risk of disease progression or death by 30% (HR, 0.697; 95% CI, 0.387-0.768; P = .0018). The efficacy of elacestrant was even more pronounced among patients with ESR1 mutations, with a 45% reduction in the risk of disease progression or death (HR, 0.546; 95% CI, 0.387-0.768; P = .0005). In an interim OS analysis, elacestrant also showed a trend toward improved OS among all patients and in patients with ESR1 mutations.8

Other ongoing trials of novel endocrine therapies are exclusively enrolling patients with ESR1 mutations. Lasofoxifene, which is leading the pack for novel SERMs in clinical development, is currently being evaluated in the phase 2 ELAINE and ELAINE-2 trials (NCT04432454). In the former, lasofoxifene is being compared against fulvestrant in patients with ESR1-mutant, ER-positive, HER2-negative metastatic breast cancer that has progressed following treatment with a combination of an AI and a CDK4/6 inhibitor. In ELAINE-2, lasofoxifene is combined with abemaciclib in a similar setting.31,32

References

  1. Inwald EC, Klinkhammer-Schalke M, Hofstädter F, et al. Ki-67 is a prognostic parameter in breast cancer patients: results of a large population-based cohort of a cancer registry. Breast Cancer Res Treat. 2013;139(2):539-552. doi:10.1007/s10549-013-2560-8
  2. Nielsen TO, Leung SCY, Rimm DL, et al. Assessment of Ki67 in breast cancer: updated recommendations from the International Ki67 in Breast Cancer Working Group. J Nat Cancer Inst. Published online December 28, 2020. doi:10.1093/jnci/djaa201
  3. Kuemmel S, Gluz O, Nitz U, et al; West German Study Group. Neoadjuvant nab-paclitaxel weekly versus dose-dense paclitaxel followed by dose-dense EC in high risk HR+/HER2- early BC by: results from the neoadjuvant part of ADAPT HR+/HER2- trial.Cancer Res. 2021;81(suppl 4):GS4-03. doi:10.1158/1538-7445.SABCS20-GS4-03
  4. Harbeck N, Gluz O, Kuemmel S, et al; West German Study Group. Endocrine therapy alone in patients with intermediate or high-risk luminal early breast cancer (0-3 lymph nodes), recurrence score <26 and Ki67 response after preoperative endocrine therapy: primary outcome results from the WSG-ADAPT HR+/HER2- trial. Presented at: 2020 San Antonio Breast Cancer Symposium. December 8-12, 2020; Virtual. Abstract GS4-04.
  5. Harbeck N, Johnston S, Fasching P, et al. High Ki-67 as a biomarker for identifying patients with high risk early breast cancer treated in monarchE. Cancer Res. 2021;81(suppl 4):PD2-01. doi:10.1158/1538-7445.SABCS20-PD2-01
  6. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70. doi:10.1016/s0092-8674(00)81683-9
  7. Menon SS, Guruvayoorappan C, Sakthivel KM, Rasmi RR. Ki-67 protein as a tumour proliferation marker. Clin Chim Acta. 2019;491:39-45. doi:10.1016/j.cca.2019.01.011
  8. Penault-Llorca F, Radosevic-Robin N. Ki67 assessment in breast cancer: an update. Pathology. 2017;49(2):166-171. doi:10.1016/j.pathol.2016.11.006
  9. Guadagno E, D’Avella E, Cappabianca P, Colao A, Del Basso De Caro M. Ki67 in endocrine neoplasms: to count or not to count, this is the question! A systematic review from the English language literature. J Endocrinol Invest. 2020;43(10):1429-1445. doi:10.1007/s40618-020-01275-9
  10. Luo Y, Ren F, Liu Y, et al. Clinicopathological and prognostic significance of high Ki-67 labeling index in hepatocellular carcinoma patients: a meta-analysis. Int J Clin Exp Med. 2015;8(7):10235-10247.
  11. Ko K, Jeong CW, Kwak C, Kim HH, Ku JH. Significance of Ki-67 in non–muscle invasive bladder cancer patients: a systematic review and meta-analysis. Oncotarget. 2017;8(59):100614-100630. doi:10.18632/oncotarget.21899
  12. Fisher G, Yang ZH, Kudahetti S, et al. Prognostic value of Ki-67 for prostate cancer death in a conservatively managed cohort. Br J Cancer. 2013;108(2):271-277. doi:10.1038/bjc.2012.598
  13. Verma R, Gupta V, Singh J, et al. Significance of p53 and ki-67 expression in prostate cancer. Urol Ann. 2015;7(4):488-493. doi:10.4103/0974-7796.158507
  14. Tanaka K, Hasegawa T, Nojima T, et al. Prospective evaluation of Ki-67 system in histological grading of soft tissue sarcomas in the Japan Clinical Oncology Group Study JCOG0304. World J Surg Oncol. 2016;14:110. doi:10.1186/s12957-016-0869-6
  15. Telugu RB, Chowhan AK, Rukmangadha N, et al. Histopathological and immunohistochemical evaluation of meningiomas with reference to proliferative markers p53 and Ki-67. J Clin Diagn Res. 2016;10(1):EC15-EC19. doi:10.7860/JCDR/2016/15661.7117
  16. Giuliano AE, Connolly JL, Edge SB, et al. Breast cancer—major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin. 2017;67(4):290-303. doi:10.3322/caac.21393
  17. Yerushalmi R, Woods R, Ravdin PM, Hayes MM, Gelmon KA. Ki67 in breast cancer: prognostic and predictive potential. Lancet Oncol. 2010;11(2):174-183. doi:10.1016/S1470-2045(09)70262-1
  18. Ades F, Zardavas D, Bozovic-Spasojevic I, et al. Luminal B breast cancer: molecular characterization, clinical management, and future perspectives. J Clin Oncol. 2014;32(25):2794-2803. doi:10.1200/JCO.2013.54.1870
  19. Cheang MCU, Chia SK, Voduc D, et al. Ki67 index, HER2 status, and prognosis of patients with luminal B breast cancer. J Natl Cancer Inst. 2009;101(10):736-750. doi:10.1093/jnci/djp082
  20. Feeley LP, Mulligan AM, Pinnaduwage D, Bull SB, Andrulis IL. Distinguishing luminal breast cancer subtypes by Ki67, progesterone receptor or TP53 status provides prognostic information. Mod Pathol. 2014;27(4):554-561. doi:10.1038/modpathol.2013.153
  21. Goldhirsch A, Wood WC, Coates AS, Gelber RD, Thürlimann B, Senn HJ; Panel members. Strategies for subtypes—dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011;22(8):1736-1747. doi:10.1093/annonc/mdr304
  22. Goldhirsch A, Winer EP, Coates AS, et al; Panel members. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24(9):2206-2223. doi:10.1093/annonc/mdt303
  23. Krop I, Ismaila N, Andre F, et al. Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline focused update. J Clin Oncol. 2017;35(24):2838-2847. doi:10.1200/JCO.2017.74.0472
  24. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 1.2021. Accessed January 29, 2021. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
  25. Leung SCY, Nielsen TO, Zabaglo L, et al; International Ki67 in Breast Cancer Working Group of the Breast International Group and North American Breast Cancer Group (BIG-NABCG). Analytical validation of a standardized scoring protocol for Ki67: phase 3 of an international multicenter collaboration. NPJ Breast Cancer. 2016;2:16014. doi:10.1038/npjbcancer.2016.14
  26. Cortazar P, Zhang L, Untch M, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384(9938):164-172. doi:10.1016/S0140-6736(13)62422-8
  27. Dowsett M, Smith IE, Ebbs SR, et al; IMPACT Trialists Group. Prognostic value of Ki67 expression after short-term presurgical endocrine therapy for primary breast cancer. J Natl Cancer Inst. 2007;99(2):167-170. doi:10.1093/jnci/djk020
  28. Dowsett M, Smith IE, Ebbs SR, et al; IMPACT Trialists. Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin Cancer Res. 2005;11(2):951s-958s.
  29. Smith I, Robertson J, Kilburn L, et al. Long-term outcome and prognostic value of Ki67 after perioperative endocrine therapy in postmenopausal women with hormone-sensitive early breast cancer (POETIC): an open-label, multicentre, parallel-group, randomised, phase 3 trial. Lancet Oncol. 2020;21(11):1443-1454. doi:10.1016/S1470-2045(20)30458-7
  30. Interpreting the results. Oncotype IQ. Accessed January 29, 2021. https://www.oncotypeiq.com/en-US/breast-cancer/healthcare-professionals/oncotype-dx-breast-recurrence-score/interpreting-the-results
  31. About the Oncoytpe DX Breast Recurrence Score test. Oncotype IQ. Accessed January 29, 2021. https://www.oncotypeiq.com/en-US/breast-cancer/healthcare-professionals/oncotype-dx-breast-recurrence-score/about-the-test
  32. Suman VJ, Ellis MJ, Ma CX. The ALTERNATE trial: assessing a biomarker driven strategy for the treatment of post-menopausal women with ER+/Her2− invasive breast cancer. Chin Clin Oncol. 2015;4(3):34. doi:10.3978/j.issn.2304-3865.2015.09.01
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