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. 2022 Aug 1;8(8):1177-1183.
doi: 10.1001/jamaoncol.2022.2286.

Prognostic and Biologic Significance of ERBB2-Low Expression in Early-Stage Breast Cancer

Paolo Tarantino  1   2   3   4 , Qingchun Jin  5 , Nabihah Tayob  2   5 , Rinath M Jeselsohn  1   2 , Stuart J Schnitt  1   2   6 , Julie Vincuilla  1 , Tonia Parker  1 , Svitlana Tyekucheva  2   5 , Tianyu Li  5 , Nancy U Lin  1   2 , Melissa E Hughes  1 , Anna C Weiss  1   2   7 , Tari A King  1   2   7 , Elizabeth A Mittendorf  1   2   7 , Giuseppe Curigliano  3   4 , Sara M Tolaney  1   2
Affiliations

Prognostic and Biologic Significance of ERBB2-Low Expression in Early-Stage Breast Cancer

Paolo Tarantino et al. JAMA Oncol. .

Abstract

Importance: It is unclear whether ERBB2-low breast cancer should be considered an individual biologic subtype distinct from ERBB2-0 breast cancer.

Objective: To investigate whether low ERBB2 expression is associated with distinct clinicopathologic characteristics and prognosis among patients with hormone receptor (HR)-positive and triple-negative breast cancer (TNBC).

Design, setting, and participants: This cohort study was conducted using data from a prospectively maintained institutional database on all consecutive patients with breast cancer undergoing surgery between January 2016 and March 2021 at Dana-Farber Brigham Cancer Center. The study included 5235 patients with stage I through III, ERBB2-negative invasive breast cancer. Tumors were classified as ERBB2-low if they had an ERBB2 immunohistochemical (IHC) score of 1+ or 2+ with negative in situ hybridization assay and ERBB2-0 if they had an ERBB2 IHC score of 0. Data were analyzed from September 2021 through January 2022.

Exposures: Standard treatment according to institutional guidelines.

Main outcomes and measures: Comparison of clinicopathologic characteristics and disease outcomes (pathologic complete response rate [pCR], disease-free survival, distant disease-free survival, and overall survival) between patients with ERBB2-low and ERBB2-0 breast cancer.

Results: Among 5235 patients with ERBB2-negative invasive breast cancer (5191 [99.2%] women; median [range] age at primary surgery, 59.0 [21.0-95.0] years), 2917 patients (55.7%) and 2318 patients (44.3%) had ERBB2-low and ERBB2-0 tumors, respectively. Expression of HR was significantly more common among ERBB2-low compared with ERBB2-0 tumors (2643 patients [90.6%] vs 1895 patients [81.8%]; P < .001). The rate of ERBB2-low tumors increased progressively, from 296 of 739 estrogen receptor (ER)-negative tumors (40.1%) to 31 of 67 ER-low (ie, ER 1%-9%) tumors (46.3%), 37 of 67 ER-moderate (ie, ER, 10%-49%) tumors (55.2%), 2047 of 3542 ER-high (ie, ER, 50%-95%) tumors (57.8%), and 499 of 803 ER-very high (ie, ER > 95%) tumors (62.1%) (P < .001). Among 675 patients receiving neoadjuvant chemotherapy, those with ERBB2-0 tumors experienced higher pCR rates (95 patients [26.8%] vs 53 patients [16.6%]; P = .002). However, there were no statistically significant differences in pCR rate between ERBB2-low and ERBB2-0 tumors when separately analyzing HR-positive, ER-low, HR-positive without ER-low, or TNBC tumors. In exploratory survival analysis, no differences by ERBB2-low expression in disease-free survival, distant disease-free survival, or overall survival were observed among patients with HR-positive tumors or TNBC.

Conclusions and relevance: The results of this cohort study did not support the interpretation of ERBB2-low breast cancer as a distinct biologic subtype. ERBB2-low expression was positively associated with level of ER expression, and ER-low tumors were enriched among ERBB2-0 tumors, suggesting that, given the worse prognosis of ER-low tumors, they may be associated with confounding of prognostic analyses of ERBB2-low expression.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Tarantino reported receiving consulting fees from AstraZeneca during the conduct of the study. Dr Jeselsohn reported receiving grants from Lilly, research funding from Pfizer, and personal fees from Luminex outside the submitted work. Dr Lin reported receiving personal fees from AstraZeneca and Seagen and grants from Genentech, Merck, Pfizer, and Seagen outside the submitted work. Dr Weiss reported receiving research funding from Myriad Laboratories. Dr King reported receiving speaker honoraria and serving on advisory boards for Exact Sciences, formerly Genomic Health. Dr Mittendorf reported receiving personal fees from Merck, Genentech/Roche, and Exact Sciences and participating in trial steering committees for Bristol Myers Squibb, Lilly, and Genentech/Roche outside the submitted work. Dr Curigliano reported receiving personal fees from Roche, Daiichi Sankyo, AstraZeneca, Lilly, Novartis, Pfizer, Celcuity, Exact Sciences, Ellipsis, and Bristol Myers Squibb outside the submitted work. Dr Tolaney reported receiving personal fees from Novartis, Lilly, Pfizer, Merck, AstraZeneca, Eisai, Puma, Genentech/Roche, Immunomedics/Gilead, Nektar, Tesaro, Daiichi Sankyo, Athenex, Bristol Myers Squibb, NanoString, Sanofi, Odonate Therapeutics, Seagen, Exelixis, Cyclacel, OncoPep, Kyowa Kirin, Samsung Bioepis, CytomX, Certara, Mersana Therapeutics, Ellipses Pharma, 4D Pharma, OncoSec, Medical Incorporated, Chugai Pharmaceutical, BeyondSpring, OncXerna, Zymeworks, and Zentalis Pharmaceuticals outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Proportion of ERBB2-Low Tumors by Estrogen Receptor (ER) Expression Threshold
A progressive increase in the proportion of ERBB2-low–expressing tumors was observed with increasing thresholds of ER expression (P < .001). Most triple-negative breast cancers and ER-low–expressing tumors were ERBB2-0, whereas most ER-high–expressing tumors were ERBB2-low expressing.
Figure 2.
Figure 2.. Pathologic Complete Response (pCR) Rate by ERBB2 Expression and Hormone Receptor (HR) Status
In univariate analysis, a significantly higher pCR rate, defined as ypT0/isN0, was found among ERBB2-0 tumors compared with estrogen receptor (ER)-low tumors. However, when analyzing pCR rates in different clinically relevant subgroups, no statistically significant differences in pCR were observed between ERBB2-low and ERBB2-0 tumors among HR-positive, HR-positive excluding ER-low, ER-low, or triple-negative breast cancer (TNBC) tumors.
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Comment in

References

    1. Pernas S, Tolaney SM. Management of early-stage human epidermal growth factor receptor 2-positive breast cancer. JCO Oncol Pract. 2021;17(6):320-330. doi:10.1200/OP.21.00020 - DOI - PubMed
    1. Martínez-Sáez O, Prat A. Current and future management of HER2-positive metastatic breast cancer. JCO Oncol Pract. 2021;17(10):594-604. doi:10.1200/OP.21.00172 - DOI - PubMed
    1. Tarantino P, Trapani D, Curigliano G. Mastering the use of novel anti-HER2 treatment options. JCO Oncol Pract. 2021;17(10):605-606. doi:10.1200/OP.21.00216 - DOI - PubMed
    1. Fehrenbacher L, Cecchini RS, Geyer CE Jr, et al. . NSABP B-47/NRG oncology phase III randomized trial comparing adjuvant chemotherapy with or without trastuzumab in high-risk invasive breast cancer negative for HER2 by FISH and with IHC 1+ or 2. J Clin Oncol. 2020;38(5):444-453. doi:10.1200/JCO.19.01455 - DOI - PMC - PubMed
    1. Gianni L, Lladó A, Bianchi G, et al. . Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010;28(7):1131-1137. doi:10.1200/JCO.2009.24.1661 - DOI - PMC - PubMed

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