Approximately 50% of HER2-negative breast cancers (BC) show HER2-low expression. It is unclear however whether HER2-low BC should be considered an individual biologic entity, prognostically distinct from HER2-zero BC.
Data were collected from an institutional database including all consecutive patients with BC who underwent surgery at Dana-Farber Brigham Cancer Center from 1/2016 to 3/2021. Tumors were defined as HER2-low if they had a HER2 IHC score of 1+ or 2+ with negative FISH, and HER2-zero if they had a HER2 IHC score of 0. Clinicopathologic characteristics and disease outcomes were compared between the two cohorts.
5235 HER2-negative BC patients were eligible for analysis; 4429 estrogen receptor (ER)+, 67 ER-low (1-9%), 739 ER-negative. Hormone receptor(HR)-expression was significantly more common among HER2-low compared with HER2-zero BC (89.9% vs 80.9%, p<0.001). Most other clinicopathological differences were explained by the different rate of HR+ tumors. When evaluated as a continuous variable, ER expression was significantly associated with HER2 expression (p<0.001), and the rate of HER2-low tumors increased progressively with increasing ER expression (Table). Among patients receiving neoadjuvant chemotherapy (n=657), those with HER2-zero tumors had higher pCR rates compared with HER2-low (27% vs 17%, p=0.002). However, statistical difference was lost when separately analyzing HR+ (8% vs 14%, p=0.078), ER-low (25% vs 38.9%, p=0.46), HR+ without ER-low (6.9% vs 10.4%, p=0.277), TNBC (30.8% vs 35.4%, p=0.40) and when adjusting for confounders. No difference in disease-free survival or overall survival was observed among patients with HR+ tumors or TNBC depending on HER2-low expression. Table: 1MO
Proportion of tumors with HER2-low versus HER2-zero expression according to tumor subtype and ER expression
|TNBC||ER-low (1-9%)||ER-moderate (10-49%)||ER-high (50-95%)||ER-very-high (>95%)|
Our results do not support the interpretation of HER2-low BC as a distinct biologic subtype. HER2-low expression is continuously associated with the level of ER expression. ER-low tumors are enriched among HER2-zero cases and may confound prognostic analyses.
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P. Tarantino: Financial Interests, Personal, Advisory Role: AstraZeneca. N.U. Lin: Financial Interests, Institutional, Other: Genentech, Merck, Pfizer; Financial Interests, Personal, Other: Seattle Genetics; Financial Interests, Personal, Advisory Role: Puma, Daiichi Sankyo, AstraZeneca, Denali Therapeutics, California Institute for Regenerative Medicine, Prelude Therapeutics. T.A. King: Financial Interests, Personal, Invited Speaker: Exact Sciences; Financial Interests, Personal, Advisory Role: PrecisCA Cancer Information Service. E.A. Mittendorf: Financial Interests, Personal, Advisory Role: Exact Science, Bristol Myers Squib, Genentech/Roche, Lilly, Merck. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer; Financial Interests, Personal, Advisory Board: Ellipsis, Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Non-Financial Interests, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Invited Speaker, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori. S.M. Tolaney: Financial Interests, Personal, Advisory Board, Ad Board Participant/Consultant: AstraZeneca, Eli Lilly, Pfizer, Novartis, Merck, Gilead, Genentech/Roche, Eisai, Sanofi, Seagen, Daiichi Sankyo, 4D Pharma, Puma; Financial Interests, Personal, Other, Consultant: Nektar, NanoString, Athenex, Blueprint Medicines; Financial Interests, Personal, Advisory Board, Ad board participant: Bristol Myers Squibb, OncoPep, OncoSec, Certara, Mersana Therapeutics, Ellipses Pharma, G1 Therapeutics; Financial Interests, Personal, Advisory Board, Ad board participant/consultant/DSMC: Odonate; Financial Interests, Personal, Other, Steering Committee Member/Consultant: CytomX; Financial Interests, Personal, Invited Speaker, Invited Speaker for Pharma Supported Educational Activity: Chugai Pharmaceuticals; Financial Interests, Personal, Advisory Board, Advisory Board Participation: Zymeworks, Zentalis, Reveal Genomics, OncXerna; Financial Interests, Institutional, Funding: AstraZeneca, Eli Lilly, Pfizer, Sanofi, Seagen, Odonate, Cyclacel, Exelixis, Gilead, Bristol Myers Squibb, Eisai, Merck, Novartis, Nektar, Genentech/Roche; Financial Interests, Personal and Institutional, Invited Speaker: CytomX. All other authors have declared no conflicts of interest.