Prognostic and Predictive Significance of HER2-low Expression in Metastatic Hormone Receptor Positive Breast Cancer Patients Receiving CDK4-6 Inhibitor Therapy

Hacı Arak; Tülay Kuş

doi:10.58600/eurjther2151

Authors

Hacı Arak Department of Medical Oncology, Gaziantep City Hospital, Gaziantep, Türkiye https://orcid.org/0000-0002-2023-423X
Tülay Kuş Department of Medical Oncology, Gaziantep City Hospital, Gaziantep, Türkiye https://orcid.org/0000-0001-5781-4820

DOI:

https://doi.org/10.58600/eurjther2151

Keywords:

Breast cancer, Cyclin-Dependent Kinases, Human Epidermal Growth Factor Receptor 2.

Abstract

Objective: This study aimed to analyze the predictive and prognostic value of HER2-low expression in hormone receptor (HR) positive human epidermal growth factor receptor-2 (HER2) negative metastatic breast cancer patients receiving cyclin-dependent kinase-4/6 inhibitor (CDK4/6i) therapy.

Methods: This retrospective study included patients who received CDK4/6i plus endocrine therapy (ET). The pathological and clinical characteristics and survival times of the patients were compared and analyzed.

Results: Our study included 122 patients. There were HER2-zero 88(72%) and HER2-low 34 (28%) patients. The median progression free survival (mPFS) of all patients who received CDK4/6i+ET was 21 (95% confidence interval (CI),18.5–23.5) months, while mPFS was not reached in the HER2-zero group, and mPFS in the HER2-low group was 12 (95%CI, 6.8–17.1) months (p=0.001). The mPFS was shorter in patients with primary endocrine resistance (6 vs. 21 months, p=0.001). There was a change in the HER2-low status of 26(45%) patients with recurrence compared to the first biopsy. In the HER2-zero and HER2-low groups, 22(25%) and 24(71%) patients, respectively, progressed with CDK4/6i+ET (p=0.001). Estrogen receptor (ER) levels less than and greater than 50% resulted different mPFS (6 and 21 months, respectively) (p=0.025). Median PFS differed based on CDK4/6i+ET combination, treatment line, and best treatment response (all p=0.001). In multivariate analysis, HER2 status(p=0.018), chemotherapy status(p=0.006), best response status with CDK4/6i (p=0.001) for PFS, and best response status with CDK4/6i therapy (p=0.007) for OS were significant.

Conclusions: In patients with HR+HER- metastatic breast cancer receiving CDK4/6i therapy, the duration of mPFS was lower in the HER2-low group than that in the HER2-zero group. HER2-low expression is a predictive biomarker of response to CDK4/6 inhibitor therapy.

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References

Siegel RL, Miller KD, Fuchs HE, Jemal A (2022) Cancer statistics, 2022. CA Cancer J Clin 72:7-33. https://doi.org/10.3322/caac.21708

Prat A, Pineda E, Adamo B, Galvan P, Fernandez A, Gaba L, Diez M, Viladot M, Arance A, Munoz M (2015) Clinical implications of the intrinsic molecular subtypes of breast cancer. Breast 24 Suppl 2:S26-35. https://doi.org/10.1016/j.breast.2015.07.008

Wolff AC, Hammond MEH, Allison KH, Harvey BE, Mangu PB, Bartlett JMS, Bilous M, Ellis IO, Fitzgibbons P, Hanna W, Jenkins RB, Press MF, Spears PA, Vance GH, Viale G, McShane LM, Dowsett M (2018) Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Arch Pathol Lab Med 142:1364-1382. https://doi.org/10.5858/arpa.2018-0902-SA

Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E, Tsurutani J, Ueno NT, Prat A, Chae YS, Lee KS, Niikura N, Park YH, Xu B, Wang X, Gil-Gil M, Li W, Pierga JY, Im SA, Moore HCF, Rugo HS, Yerushalmi R, Zagouri F, Gombos A, Kim SB, Liu Q, Luo T, Saura C, Schmid P, Sun T, Gambhire D, Yung L, Wang Y, Singh J, Vitazka P, Meinhardt G, Harbeck N, Cameron DA, Investigators DE-BT (2022) Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med 387:9-20. https://doi.org/10.1056/NEJMoa2203690

Gampenrieder SP, Dezentje V, Lambertini M, de Nonneville A, Marhold M, Le Du F, Cortes Salgado A, Alpuim Costa D, Vaz Batista M, Chic Ruche N, Tinchon C, Petzer A, Blondeaux E, Del Mastro L, Targato G, Bertucci F, Goncalves A, Viret F, Bartsch R, Mannsbart C, Deleuze A, Robert L, Saavedra Serrano C, Gion Cortes M, Sampaio-Alves M, Vitorino M, Pecen L, Singer C, Harbeck N, Rinnerthaler G, Greil R, Group AS (2023) Influence of HER2 expression on prognosis in metastatic triple-negative breast cancer-results from an international, multicenter analysis coordinated by the AGMT Study Group. ESMO Open 8:100747. https://doi.org/10.1016/j.esmoop.2022.100747

Tan R, Ong WS, Lee KH, Lim AH, Park S, Park YH, Lin CH, Lu YS, Ono M, Ueno T, Naito Y, Onishi T, Lim GH, Tan SM, Lee HB, Ryu HS, Han W, Tan VKM, Wong FY, Im SA, Tan PH, Chan JY, Yap YS (2022) HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis. BMC Med 20:105. https://doi.org/10.1186/s12916-022-02284-6

Ergun Y, Ucar G, Akagunduz B (2023) Comparison of HER2-zero and HER2-low in terms of clinicopathological factors and survival in early-stage breast cancer: A systematic review and meta-analysis. Cancer Treat Rev 115:102538. https://doi.org/10.1016/j.ctrv.2023.102538

Giuliano M, Trivedi MV, Schiff R (2013) Bidirectional Crosstalk between the Estrogen Receptor and Human Epidermal Growth Factor Receptor 2 Signaling Pathways in Breast Cancer: Molecular Basis and Clinical Implications. Breast Care (Basel) 8:256-262. https://doi.org/10.1159/000354253

Douganiotis G, Kesisis G, Lalla E, Korantzis I, Boukovinas I, Papazisis K (2022) Prognostic Significance of Low HER2 Expression in Patients With Metastatic Hormone Receptor-positive Breast Cancer Treated With First Line CDK4/6 Inhibitors: A Greek Multicenter Real-world Data Analysis. Cancer Diagn Progn 2:585-591. https://doi.org/10.21873/cdp.10146

Carlino F, Diana A, Ventriglia A, Piccolo A, Mocerino C, Riccardi F, Bilancia D, Giotta F, Antoniol G, Famiglietti V, Feliciano S, Cangiano R, Lobianco L, Pellegrino B, De Vita F, Ciardiello F, Orditura M (2022) HER2-Low Status Does Not Affect Survival Outcomes of Patients with Metastatic Breast Cancer (MBC) Undergoing First-Line Treatment with Endocrine Therapy plus Palbociclib: Results of a Multicenter, Retrospective Cohort Study. Cancers (Basel) 14. https://doi.org/10.3390/cancers14204981

Bao KKH, Sutanto L, Tse SSW, Man Cheung K, Chan JCH (2021) The Association of ERBB2-Low Expression With the Efficacy of Cyclin-Dependent Kinase 4/6 Inhibitor in Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer. JAMA Netw Open 4:e2133132. https://doi.org/10.1001/jamanetworkopen.2021.33132

Cardoso F, Senkus E, Costa A, Papadopoulos E, Aapro M, Andre F, Harbeck N, Aguilar Lopez B, Barrios CH, Bergh J, Biganzoli L, Boers-Doets CB, Cardoso MJ, Carey LA, Cortes J, Curigliano G, Dieras V, El Saghir NS, Eniu A, Fallowfield L, Francis PA, Gelmon K, Johnston SRD, Kaufman B, Koppikar S, Krop IE, Mayer M, Nakigudde G, Offersen BV, Ohno S, Pagani O, Paluch-Shimon S, Penault-Llorca F, Prat A, Rugo HS, Sledge GW, Spence D, Thomssen C, Vorobiof DA, Xu B, Norton L, Winer EP (2018) 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)dagger. Ann Oncol 29:1634-1657. https://doi.org/10.1093/annonc/mdy192

Baez-Navarro X, van Bockstal MR, Andrinopoulou ER, van Deurzen CHM (2023) HER2-Low Breast Cancer: Incidence, Clinicopathologic Features, and Survival Outcomes From Real-World Data of a Large Nationwide Cohort. Mod Pathol 36:100087. https://doi.org/10.1016/j.modpat.2022.100087

Shi Q, Yu J, Liu D, Ren F, Wu J, Shen K (2023) Distribution, dynamic evolution, and clinical outcomes of patients with advanced breast cancer according to HER2 expression. BMC Cancer 23:173. https://doi.org/10.1186/s12885-023-10634-7

Stanciu IM, Parosanu AI, Orlov-Slavu C, Iaciu IC, Popa AM, Olaru CM, Pirlog CF, Vrabie RC, Nitipir C (2023) Mechanisms of Resistance to CDK4/6 Inhibitors and Predictive Biomarkers of Response in HR+/HER2-Metastatic Breast Cancer-A Review of the Literature. Diagnostics (Basel) 13. https://doi.org/10.3390/diagnostics13050987

Mazumder A, Shiao S, Haricharan S (2021) HER2 Activation and Endocrine Treatment Resistance in HER2-negative Breast Cancer. Endocrinology 162. https://doi.org/10.1210/endocr/bqab153

Hu Y, Gao J, Wang M, Li M (2021) Potential Prospect of CDK4/6 Inhibitors in Triple-Negative Breast Cancer. Cancer Manag Res 13:5223-5237. https://doi.org/10.2147/CMAR.S310649

Buller W, Pallan L, Chu T, Khoja L (2023) CDK4/6 inhibitors in metastatic breast cancer, a comparison of toxicity and efficacy across agents in a real-world dataset. J Oncol Pharm Pract 29:1825-1835. https://doi.org/10.1177/10781552231163121

Knudsen ES, Schultz E, Hamilton D, Attwood K, Edge S, O'Connor T, Levine E, Witkiewicz AK (2022) Real-World Experience with CDK4/6 Inhibitors for Metastatic HR+/HER2- Breast Cancer at a Single Cancer Center. Oncologist 27:646-654. https://doi.org/10.1093/oncolo/oyac089

Bartlett JM, Brookes CL, Robson T, van de Velde CJ, Billingham LJ, Campbell FM, Grant M, Hasenburg A, Hille ET, Kay C, Kieback DG, Putter H, Markopoulos C, Kranenbarg EM, Mallon EA, Dirix L, Seynaeve C, Rea D (2011) Estrogen receptor and progesterone receptor as predictive biomarkers of response to endocrine therapy: a prospectively powered pathology study in the Tamoxifen and Exemestane Adjuvant Multinational trial. J Clin Oncol 29:1531-1538. https://doi.org/10.1200/JCO.2010.30.3677

Cristofanilli M, Turner NC, Bondarenko I, Ro J, Im SA, Masuda N, Colleoni M, DeMichele A, Loi S, Verma S, Iwata H, Harbeck N, Zhang K, Theall KP, Jiang Y, Bartlett CH, Koehler M, Slamon D (2016) Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial. Lancet Oncol 17:425-439. https://doi.org/10.1016/S1470-2045(15)00613-0

Slamon DJ, Neven P, Chia S, Fasching PA, De Laurentiis M, Im SA, Petrakova K, Bianchi GV, Esteva FJ, Martin M, Nusch A, Sonke GS, De la Cruz-Merino L, Beck JT, Pivot X, Vidam G, Wang Y, Rodriguez Lorenc K, Miller M, Taran T, Jerusalem G (2018) Phase III Randomized Study of Ribociclib and Fulvestrant in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: MONALEESA-3. J Clin Oncol 36:2465-2472. https://doi.org/10.1200/JCO.2018.78.9909

Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ (2015) The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol 16:25-35. https://doi.org/10.1016/S1470-2045(14)71159-3

Gampenrieder SP, Rinnerthaler G, Tinchon C, Petzer A, Balic M, Heibl S, Schmitt C, Zabernigg AF, Egle D, Sandholzer M, Singer CF, Roitner F, Hager C, Andel J, Hubalek M, Knauer M, Greil R (2021) Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry. Breast Cancer Res 23:112. https://doi.org/10.1186/s13058-021-01492-x