Final results of a 2:1 control-case observational study using interferon beta and interleukin-2, in addition to first-line hormone therapy, in estrogen receptor-positive, endocrine-responsive metastatic breast cancer patients

Abstract

Aim: We conducted a pilot study that combines immunotherapy (cyclic interleukin-2 interferon-beta sequence) and hormone therapy (HT) to overcome endocrine resistance in metastatic breast cancer.

Methods: The final results of a 2:1 control-case retrospective observational study are here shown following 22 additional months of postoperative follow-up and 6 further controls. There were 95 controls and 42 cases in total. The 95 controls were ER+/HER2- metastatic breast cancer patients who underwent first-line HT with aromatase inhibitors (AIs) or fulvestrant. Twenty-eight of them (28.9%) also received biological drugs including cyclin kinase inhibitors (CKIs). The 42 cases were ER+ metastatic breast cancer patients who received interferon beta-interleukin-2 immunotherapy in addition to first-line HT. Selective estrogen receptor modulators/down-regulators (SERMs/SERDs) were used for HT in 39 (92.9%) of them and AIs in the remaining 3.

Results: Median progression-free survival (PFS) and overall survival (OS) were significantly longer in the 42 studied patients who received hormone immunotherapy (HIT) than in the 95 controls (median time 33 vs. 18 months, P = 0.002, and 81 vs. 62 months, P = 0.019). In the analysis adjusted for disease-free interval (DFI), hormone receptor, HER2 status, visceral involvement, AIs, and biological therapy, the PFS and OS hazard ratio (HR) further increased in favor of the 42 cases (P = 0.004 and P = 0.044 respectively). In the same ER+/HER2- metastatic breast cancer patients treated with both AIs and CKIs, a median PFS ranging from 25.3 to 28.18 months and a median OS of 37.5 months were observed.

Conclusions: This study strongly suggests multi-center randomized clinical trials should be performed to enter our proposed immunotherapy into clinical practice.

Keywords

Breast cancer / metastasis / hormone-dependent / hormone resistance / immunotherapy

References

[1] Howlader N,Li CI.US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status.J Natl Cancer Inst2014;106:dju055 PMCID:PMC4580552

[2] Parise CA,Brown MM.Breast cancer subtypes as defined by the estrogen receptor (ER), progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) among women with invasive breast cancer in California, 1999-2004.Breast J2009;15:593-602

[3] Senkus E,Pagani O.Time for more optimism in metastatic breast cancer?.Cancer Treat Rev2014;40:220-8

[4] Vonderheide RH,Clark AS.Immunotherapy for breast cancer: what are we missing?.Clin Cancer Res2017;23:2640-6 PMCID:PMC5480967

[5] Caswell-Jin JL,Tian L.Change in survival in metastatic breast cancer with treatment advances: meta-analysis and systematic review.JNCI Cancer Spectr2018;2:pky062 PMCID:PMC6305243

[6] Nayar U,Kapstad C.Acquired HER2 mutations in ER⁺ metastatic breast cancer confer resistance to estrogen receptor-directed therapies.Nat Genet2019;51:207-16

[7] AlFakeeh A.Overcoming endocrine resistance in hormone receptor-positive breast cancer.Curr Oncol2018;25:S18-27 PMCID:PMC6001756

[8] Najim O,Sergoynne L.The association between type of endocrine therapy and development of estrogen receptor-1 mutation(s) in patients with hormone-sensitive advanced breast cancer: a systematic review and meta-analysis of randomized and non-randomized trials.Biochim Biophys Acta Rev Cancer2019;1872:188315

[9] Piezzo M,Caputo R.Targeting cell cycle in breast cancer: CDK4/6 inhibitors.Int J Mol Sci2020;21:6479 PMCID:PMC7554788

[10] Hortobagyi GN,Burris HA.Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer.Ann Oncol2018;29:1541-7

[11] Finn RS,Bondarenko I.Overall survival results from the randomized phase 2 study of palbociclib in combination with letrozole versus letrozole alone for first-line treatment of ER+/HER2- advanced breast cancer (PALOMA-1, TRIO-18).Breast Cancer Res Treat2020;183:419-28 PMCID:PMC7383036

[12] Johnston S,Di Leo A.Monarch 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer.NPJ Breast Cancer2019;5:5 PMCID:PMC6336880

[13] Nicolini A,Ferrari P,Rossi G.Immunotherapy and hormone-therapy in metastatic breast cancer: a review and an update.Curr Drug Targets2016;17:1127-39

[14] Nicolini A.Beta-interferon and interleukin-2 prolong more than three times the survival of 26 consecutive endocrine dependent breast cancer patients with distant metastases: an exploratory trial.Biomed Pharmacother2005;59:253-63

[15] Nicolini A,Ferrari P,Carpi A.A new immunotherapy schedule in addition to first-line hormone therapy for metastatic breast cancer patients in a state of clinical benefit during hormone therapy.J Mol Med (Berl)2020;98:375-82

[16] Available from: https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. [Last accessed on 29 Mar 2022]

[17] Available from: https://www.esmo.org/Guidelines/Breast-Cancer [Last accessed on 29 Mar 2022]

[18] Eisenhauer EA,Bogaerts J.New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1).Eur J Cancer2009;45:228-47

[19] Bast RC Jr,Hayes DF.American Society of Clinical Oncology Tumor Markers Expert Panel2000 update of recommendations for the use of tumor markers in breast and colorectal cancer: clinical practice guidelines of the American Society of Clinical Oncology.J Clin Oncol2001;19:1865-78

[20] David S,Savas P.Stereotactic ablative body radiotherapy (SABR) for bone only oligometastatic breast cancer: a prospective clinical trial.Breast2020;49:55-62 PMCID:PMC7375645

[21] Coleman RE,Rubens RD.Clinical course and prognostic factors following bone recurrence from breast cancer.Br J Cancer1998;77:336-40 PMCID:PMC2151240

[22] Pagani O,Wood W.ESO-MBC Task ForceInternational guidelines for management of metastatic breast cancer: can metastatic breast cancer be cured?.J Natl Cancer Inst2010;102:456-63 PMCID:PMC3298957

[23] Nicolini A,Morganti R.Treatment of metastatic or high-risk solid cancer patients by targeting the immune system and/or tumor burden: six cases reports.Int J Mol Sci2019;20:5986 PMCID:PMC6929121

[24] Oliver AJ,Unsworth AS.Tissue-dependent tumor microenvironments and their impact on immunotherapy responses.Front Immunol2018;9:70 PMCID:PMC5797771

[25] Lee H,Choi H.Differences in tumor immune microenvironment in metastatic sites of breast cancer.Front Oncol2021;11:649004 PMCID:PMC8013993

[26] Roato I.Cancer stem cells, bone and tumor microenvironment: key players in bone metastases.Cancers (Basel)2018;10:56 PMCID:PMC5836088

[27] Escrivá-de-Romaní S,Bellet M.HER2-positive breast cancer: Current and new therapeutic strategies.Breast2018;39:80-8

[28] Kwa MJ.Checkpoint inhibitors in triple-negative breast cancer (TNBC): Where to go from here.Cancer2018;124:2086-103

[29] Howlader N,Li CI.US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst 2014; 106(5): dju055. PMCID:PMC4580552

[30] Alberts SR,Roche PR.Comparison of estrogen receptor determinations by a biochemical ligand-binding assay and immunohistochemical staining with monoclonal antibody ER1D5 in females with lymph node positive breast carcinoma entered on two prospective clinical trials. Cancer 1996; 1978(4): 764-772. DOI: 10.1002/(SICI)1097-0142(19960815)78:4

[31] Allred DC,Daniel CO,Cruz AB Jr.Immunocytochemical analysis of estrogen receptors in human breast carcinomas. Evaluation of 130 cases and review of the literature regarding concordance with biochemical assay and clinical relevance.Arch Surg1990;125:107-13

[32] Mouridsen H,Sun Y.Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group.J Clin Oncol2003;21:2101-9

[33] Thürlimann B,Köberle D.Anastrozole (‘Arimidex’) versus tamoxifen as first-line therapy in postmenopausal women with advanced breast cancer: Results of the double-blind cross-over SAKK trial 21/95 - a sub-study of the TARGET (Tamoxifen or ‘Arimidex’ Randomized Group Efficacy and Tolerability) trial.Breast Cancer Res Treat2004;85:247-54

[34] Kim YJ,Kim IA.Molecular subtype predicts incidence and prognosis of brain metastasis from breast cancer in SEER database.J Cancer Res Clin Oncol2018;144:1803-16

[35] Kalimutho M,Mittal D,Srihari S.Targeted therapies for triple-negative breast cancer: combating a stubborn disease.Trends Pharmacol Sci2015;36:822-46

[36] Pusina S.Correlation of serum levels of urokinase activation plasminogen (uPA) and its inhibitor (PAI-1) with hormonal and HER-2 Status in the Early invasive breast cancer.Med Arch2018;72:335-40 PMCID:PMC6282918

[37] Nicolini A,Duffy MJ.Prognostic and predictive biomarkers in breast cancer: Past, present and future.Semin Cancer Biol2018;52:56-73

[38] Welte T,Rosen JM.Repurposing antiestrogens for tumor immunotherapy.Cancer Discov2017;7:17-9 PMCID:PMC5224927

[39] Nicolini A,Ferrari P.Clinical and laboratory patterns during immune stimulation in hormone responsive metastatic breast cancer.Biomed Pharmacother2014;68:171-8

[40] Lei JT,Seker S.ESR1 alterations and metastasis in estrogen receptor positive breast cancer.J Cancer Metastasis Treat2019;5:38 PMCID:PMC6519472

[41] Razavi P,Xu G.The genomic landscape of endocrine-resistant advanced breast cancers.Cancer Cell2018;34:427-438.e6 PMCID:PMC6327853