Comparison of Management and Outcomes in ERBB2-Low vs ERBB2-Zero Metastatic Breast Cancer in France

Ombline de Calbiac, Amélie Lusque, Audrey Mailliez, Thomas Bachelot, Lionel Uwer, Marie-Ange Mouret-Reynier, George Emile, Christelle Jouannaud, Anthony Gonçalves, Anne Patsouris, Véronique Diéras, Marianne Leheurteur, Thierry Petit, Paul Cottu, Jean-Marc Ferrero, Véronique D'Hondt, Isabelle Desmoulins, Joana Mourato-Ribeiro, Anne-Laure Martin, Jean-Sébastien Frenel, Ombline de Calbiac, Amélie Lusque, Audrey Mailliez, Thomas Bachelot, Lionel Uwer, Marie-Ange Mouret-Reynier, George Emile, Christelle Jouannaud, Anthony Gonçalves, Anne Patsouris, Véronique Diéras, Marianne Leheurteur, Thierry Petit, Paul Cottu, Jean-Marc Ferrero, Véronique D'Hondt, Isabelle Desmoulins, Joana Mourato-Ribeiro, Anne-Laure Martin, Jean-Sébastien Frenel

Abstract

Importance: ERBB2-low (ie, ERBB2 immunohistochemistry score of 1+ or 2+ in the absence of ERBB2 gene amplification) breast cancer (BC) is a new entity, with emerging dedicated treatments. Little is known about its prognosis and response to conventional therapy compared with ERBB2-zero breast tumors (ie, those with an immunohistochemistry score of 0).

Objective: To compare the outcomes for patients with ERBB2-low metastatic BC (MBC) with those of patients with ERBB2-zero MBC.

Design, setting, and participants: This cohort study was conducted from the Epidemiological Strategy and Medical Economics MBC platform and included patients with MBC treated between 2008 and 2016 in 18 French comprehensive cancer centers. The data analysis was conducted from July 16, 2020, to April 1, 2022.

Main outcomes and measures: The main outcome was overall survival (OS), and the secondary outcome was progression-free survival under first-line treatments (PFS1).

Results: The median (range) age was 60.0 (22.0-103.0) years. Among 15 054 patients with MBC, 4671 (31%) had ERBB2-low MBC and 10 383 (69%) had ERBB2-zero MBC. The proportion of ERBB2-low cancers was higher among patients with hormone receptor-positive MBC than those with hormone receptor-negative disease (4083 patients [33.0%] vs 588 patients [21.0%]). With a median follow-up of 49.5 months (95% CI, 48.6-50.4 months), the median OS of the ERBB2-low group was 38.0 months (95% CI, 36.4-40.5 months) compared with 33.9 months (95% CI, 32.9-34.9 months) for the ERBB2-zero group (P < .001). After adjustment for age, visceral metastases, number of metastatic sites, de novo disease, period of care, and hormone receptor status, patients with ERBB2-low MBC had slightly better OS compared with patients with ERBB2-zero MBC (adjusted hazard ratio, 0.95; 95% CI, 0.91-0.99; P = .02). In contrast, PFS1 did not differ by ERBB2 status (adjusted hazard ratio, 0.99; 95% CI, 0.95-1.02; P = .45). No significant differences in OS and PFS1 were observed in multivariate analyses by hormone receptor status and types of frontline treatment.

Conclusions and relevance: In this large cohort study, patients with ERBB2-low MBC had a slightly better OS than those with completely ERBB2-zero tumors, but identical PFS1, which could help guide treatment selection.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Bachelot reported receiving grants and personal fees from Daiichi/AstraZeneca, Pfizer, and Seattle Genetics; and personal fees from Novartis and Roche outside the submitted work. Dr Emile reported receiving personal fees from AstraZenzca and Daiichi Sankyo and nonfinancial support from Novartis, Lilly, and Roche outside the submitted work. Dr Jouannaud reported receiving honoraria from Pfizer and Daiichi Sankyo outside the submitted work. Dr Gonçalves reported receiving nonfinancial support from Novartis and grants from Pfizer and Lilly outside the submitted work. Dr Patsouris reported receiving travel support from Roche and honoraria for serving on advisory boards from Daiichi Sankyo, Lilly, and Pfizer outside the submitted work. Dr Petit reported receiving personal fees and nonfinancial support from Daiichi Sankyo during the conduct of the study. Dr Frenel reported receiving personal fees from Roche, Seattle Genetics, Novartis, Pfizer, Lilly, GlaxoSmithKline, Clovis Oncology, AstraZeneca, Daiichi Sankyo, Gilead, Merck Sharpe & Dohme, Amgen, and Pierre Fabre outside the submitted work. No other disclosures were reported.

Figures

Figure 1.. Participant Enrollment Flowchart
Figure 1.. Participant Enrollment Flowchart
CISH indicates chromogenic in situ hybridization; ESME, Epidemiological Strategy and Medical Economics; FISH, fluorescence in situ hybridization; HR, hormone receptor; MBC, metastatic breast cancer; PFS1, progression-free survival under first-line treatments.
Figure 2.. Kaplan-Meier Analysis for Overall Survival…
Figure 2.. Kaplan-Meier Analysis for Overall Survival (OS) According to ERBB2 Status (ERBB2-Low vs ERBB2-Zero)
Disease outcomes were compared among the populations of patients with ERBB2-low and ERBB2-zero tumors, with separate analyses for the overall population (A), hormone receptor–positive tumors (B), and hormone receptor–negative tumors (C). HR indicates hazard ratio.
Figure 3.. Multivariable Analyses of Overall Survival…
Figure 3.. Multivariable Analyses of Overall Survival and Progression-Free Survival in Frontline in the Overall Population, by Hormone Receptor Subgroup and by Frontline Treatment
The forest plots show the adjusted hazard ratio (HR) of ERBB2-low metastatic breast cancer compared with ERBB2-zero cancer.
Figure 4.. ERBB2 Discordance From Primary Breast…
Figure 4.. ERBB2 Discordance From Primary Breast Cancer to Metastasis in the ESME Database
The overall discordance rate from primary tumor to metastasis was 40.9% (1005 tumors).

References

    1. Wolff AC, Hammond MEH, Allison KH, et al. . Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update. J Clin Oncol. 2018;36(20):2105-2122. doi:10.1200/JCO.2018.77.8738
    1. Franchet C, Djerroudi L, Maran-Gonzalez A, et al. ; Pour le GEFPICS . Mise à jour 2021 des recommandations du GEFPICS pour l’évaluation du statut HER2 dans les cancers infiltrants du sein en France. Ann Pathol. 2021;41(6):507-520. doi:10.1016/j.annpat.2021.07.014
    1. Tarantino P, Hamilton E, Tolaney SM, et al. . HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol. 2020;38(17):1951-1962. doi:10.1200/JCO.19.02488
    1. Eiger D, Agostinetto E, Saúde-Conde R, de Azambuja E. The exciting new field of HER2-low breast cancer treatment. Cancers (Basel). 2021;13(5):1015. doi:10.3390/cancers13051015
    1. Banerji U, van Herpen CML, Saura C, et al. . Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019;20(8):1124-1135. doi:10.1016/S1470-2045(19)30328-6
    1. Modi S, Park H, Murthy RK, et al. . Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study. J Clin Oncol. 2020;38(17):1887-1896. doi:10.1200/JCO.19.02318
    1. Wang J, Liu Y, Zhang Q, et al. . RC48-ADC, a HER2-targeting antibody-drug conjugate, in patients with HER2-positive and HER2-low expressing advanced or metastatic breast cancer: a pooled analysis of two studies. J Clin Oncol. 2021;39(15)(suppl):1022-1022. doi:10.1200/JCO.2021.39.15_suppl.1022
    1. Gennari A, André F, Barrios CH, et al. ; ESMO Guidelines Committee . ESMO clinical practice guideline for the diagnosis, staging and treatment of patients with metastatic breast cancer. Ann Oncol. 2021;32(12):1475-1495. doi:10.1016/j.annonc.2021.09.019
    1. Rossi V, Sarotto I, Maggiorotto F, et al. . Moderate immunohistochemical expression of HER-2 (2+) without HER-2 gene amplification is a negative prognostic factor in early breast cancer. Oncologist. 2012;17(11):1418-1425. doi:10.1634/theoncologist.2012-0194
    1. Gilcrease MZ, Woodward WA, Nicolas MM, et al. . Even low-level HER2 expression may be associated with worse outcome in node-positive breast cancer. Am J Surg Pathol. 2009;33(5):759-767. doi:10.1097/PAS.0b013e31819437f9
    1. Jacot W, Maran-Gonzalez A, Massol O, et al. . Prognostic value of HER2-low expression in non-metastatic triple-negative breast cancer and correlation with other biomarkers. Cancers (Basel). 2021;13(23):6059. doi:10.3390/cancers13236059
    1. Denkert C, Seither F, Schneeweiss A, et al. . Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021;22(8):1151-1161. doi:10.1016/S1470-2045(21)00301-6
    1. Agostinetto E, Rediti M, Fimereli D, et al. . HER2-low breast cancer: molecular characteristics and prognosis. Cancers (Basel). 2021;13(11):2824. doi:10.3390/cancers13112824
    1. Schettini F, Chic N, Brasó-Maristany F, et al. . Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer. 2021;7(1):1. doi:10.1038/s41523-020-00208-2
    1. Li Y, Abudureheiyimu N, Mo H, et al. . In real life, low-level HER2 expression may be associated with better outcome in HER2-negative breast cancer: a study of the National Cancer Center, China. Front Oncol. 2022;11:774577. doi:10.3389/fonc.2021.774577
    1. Gampenrieder SP, Rinnerthaler G, Tinchon C, et al. . Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry. Breast Cancer Res. 2021;23(1):112. doi:10.1186/s13058-021-01492-x
    1. Cardoso F, Kyriakides S, Ohno S, et al. . Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2019;30(8):1194-1220. doi:10.1093/annonc/mdz173
    1. Miglietta F, Griguolo G, Bottosso M, et al. . Author correction: evolution of HER2-low expression from primary to recurrent breast cancer. NPJ Breast Cancer. 2021;7(1):149. doi:10.1038/s41523-021-00359-w
    1. Tarantino P, Gandini S, Nicolò E, et al. . Evolution of low HER2 expression between early and advanced-stage breast cancer. Eur J Cancer. 2022;163:35-43. doi:10.1016/j.ejca.2021.12.022
    1. Shah SP, Morin RD, Khattra J, et al. . Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution. Nature. 2009;461(7265):809-813. doi:10.1038/nature08489
    1. Marchiò C, Annaratone L, Marques A, Casorzo L, Berrino E, Sapino A. Evolving concepts in HER2 evaluation in breast cancer: heterogeneity, HER2-low carcinomas and beyond. Semin Cancer Biol. 2021;72:123-135. doi:10.1016/j.semcancer.2020.02.016
    1. Tanner M, Järvinen P, Isola J. Amplification of HER-2/neu and topoisomerase IIalpha in primary and metastatic breast cancer. Cancer Res. 2001;61(14):5345-5348.
    1. Cao N, Li S, Wang Z, et al. . NF-κB-mediated HER2 overexpression in radiation-adaptive resistance. Radiat Res. 2009;171(1):9-21. doi:10.1667/RR1472.1
    1. Won HS, Ahn J, Kim Y, et al. . Clinical significance of HER2-low expression in early breast cancer: a nationwide study from the Korean Breast Cancer Society. Breast Cancer Res. 2022;24(1):22. doi:10.1186/s13058-022-01519-x
    1. Darlix A, Louvel G, Fraisse J, et al. . Impact of breast cancer molecular subtypes on the incidence, kinetics and prognosis of central nervous system metastases in a large multicentre real-life cohort. Br J Cancer. 2019;121(12):991-1000. doi:10.1038/s41416-019-0619-y
    1. Hein A, Hartkopf AD, Emons J, et al. . Prognostic effect of low-level HER2 expression in patients with clinically negative HER2 status. Eur J Cancer. 2021;155:1-12. doi:10.1016/j.ejca.2021.06.033
    1. Riecke K, Witzel I. Targeting the human epidermal growth factor receptor family in breast cancer beyond HER2. Breast Care (Basel). 2020;15(6):579-585. doi:10.1159/000510998
    1. Modi S, Jacot W, Yamashita T, et al. ; DESTINY-Breast04 Trial Investigators . Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
    1. Fernandez AI, Liu M, Bellizzi A, et al. . Examination of low ERBB2 protein expression in breast cancer tissue. JAMA Oncol. 2022;8(4):1-4. doi:10.1001/jamaoncol.2021.7239
    1. Xu K, Bayani J, Mallon E, et al. . Discordance between immunohistochemistry and Erb-B2 receptor tyrosine kinase 2 mRNA to determine human epidermal growth factor receptor 2 low status for breast cancer. J Mol Diagn. 2022;24(7):775-783. doi:10.1016/j.jmoldx.2022.04.002

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