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. 2025 Mar 11;11(1):27.
doi: 10.1038/s41523-025-00741-y.

Dynamic HER2-low status among patients with triple negative breast cancer (TNBC) and the impact of repeat biopsies

Yael Bar  1   2 , Geoffrey Fell  3 , Aylin Dedeoglu  3 , Natalie Moffett  3 , Neelima Vidula  3   4 , Laura Spring  3   4 , Seth A Wander  3   4 , Aditya Bardia  3   5 , Naomi Ko  6 , Beverly Moy  3   4 , Leif W Ellisen  3   4 , Steven J Isakoff  3   4
Affiliations

Dynamic HER2-low status among patients with triple negative breast cancer (TNBC) and the impact of repeat biopsies

Yael Bar et al. NPJ Breast Cancer. .

Abstract

Trastuzumab deruxtecan (T-DXd) is approved for HER2-low (HER2 immunohistochemistry (IHC)1+ or 2+ with non-amplified in situ hybridization (ISH)), but not HER2-0 (IHC 0) metastatic breast cancer. The impact of repeat biopsies (Bxs) in identifying new potential candidates with triple negative breast cancer (TNBC) for T-DXd treatment remains unknown. 512 consecutive patients with TNBC at diagnosis were included in the study cohort. Bxs were categorized as core, surgical, or metastatic based on the timing and method of biopsy (Bx) acquisition, and the total number of Bxs was determined for each patient. Additionally, matched biopsies were identified, and the rate of discordance in HER2 status was calculated. The proportion of patients with at least one HER2-low result increased as the number of successive Bxs increased [59%, 73%, 83%, 83%, and 100% when 1 (196 patients), 2 (231 patients), 3 (48 patients), 4 (29 patients), and ≥ 5 (8 patients) Bxs were obtained, respectively]. Among patients without a prior HER2-low result, approximately one-third demonstrated HER2-low status with each additional successive Bx. HER2 status exhibited variability between matched Bxs, with observed discordance rates of 26%, 44%, and 33% between matched core-surgical, early-metastatic, and two metastatic matched Bxs, respectively. Our findings indicate that HER2 status can vary between different Bxs taken during the disease course of patients with TNBC with the highest discordance rate observed between the primary and metastatic Bxs. For patients with metastastic HER2-0 TNBC, repeat Bxs can increase the chance of obtaining a HER2-low result, thereby offering patients a promising therapeutic option.

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Conflict of interest statement

Competing interests: No funding was provided for this study. Individual disclosures for co-authors are as noted below:Y. B reports honoraria for lectures from Stemline, Lilly, Roche, Gilead, Pfizer, Novartis; and consulting/advisory role for Lilly, Novartis. L.W.E reports consulting/advisory role for Mersana Therapeutics, Kisoji Biotech and Astra Zeneca. L.M.S reports consultant/advisory role for Novartis, Daiichi Pharma, Astra Zeneca, Eli Lilly, Precede, Seagen; institutional research support from Merck, Genentech, Gilead, Eli Lilly, Astra Zeneca; and travel support from Eli Lilly. S.A.W reports consulting/advisory role for Foundation Medicine, Veracyte, Hologic, Eli Lilly, Biovica, Pfizer/Arvinas, Puma Biotechnology, Novartis, AstraZeneca, Genentech, Regor Therapeutics, Menarini; education/speaking fees from Eli Lilly, Guardant Health, 2ndMD; and institutional research support from Genentech, Eli Lilly, Pfizer/Arvinas, Nuvation Bio, Regor Therapeutics, Sermonix. N.V reports research funding to the institution (MGH) from Merck, Daehwa, Novartis, Pfizer, Radius, Stemline, Ellipses; and advisory board participation (all ended) for AbbVie, OncoSec, Gilead, Aadi, TerSera, Novartis, IDEOlogy Health. A.B. reports consulting or advisory Role for Pfizer, Novartis, Genentech, Merck & Co., Radius Health, Immunomedics/Gilead, Sanofi, Daiichi Pharma/AstraZeneca, Phillips, Eli Lilly and Foundation Medicine and research/grant (to institution) from Genentech, Novartis, Pfizer, Merck & Co., Sanofi, Radius Health, Immunomedics/Gilead, Daiichi Pharma/AstraZeneca and Eli Lilly. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Study design and flow diagram.
In the dashed box on the left are three representative patients. For each patient, the total number of Bxs was determined. Bxs were classified as core, surgical or metastatic and were ordered chronologically. Met metastatic, TN triple negative, ER estrogen receptor, PR progesterone receptor, Bxs biopsies, NA neoadjuvant, IHC immunohistochemistry.
Fig. 2
Fig. 2. The impact of repeat Bxs in the detection new of HER2-low results.
a The probability of detecting a HER2-low result according to the total number of Bxs conducted per patient. b The probability of detecting a first HER2-low result according to the Bx serial number. c The probability of detecting a first HER-low result for patients with prior only HER2-IHC 0 results. Bxs biopsies, pts patients, TNBC triple negative breast cancer.
Fig. 3
Fig. 3. HER2 status discordance between matched Bxs of patients with TNBC.
a HER2 status distribution according to the Bx type and ER status. b HER2 status discordance between core-surgical matched Bxs, early-metastatic matched Bxs and two metastatic matched Bxs. For the early-metastatic matched analysis, the core Bx was considered the early Bx, unless the core Bx was missing and then the surgical bx was used instead. * Significant discordance between matched Bxs. c The impact of neoadjuvant therapy on core-surgical HER2 status discordance. Matched Bxs are repeat biopsies taken from the same patient at specified time points throughout the disease course. d HER2 status discordance between matched core-surgical-metastatic Bxs. Bxs biopsies, ER estrogen receptor, TN triple negative.
See this image and copyright information in PMC

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