HER2-low is a newly defined subset of HER2-negative BC that may include up to 50% to 60% of patients previously classified as HER2-negative. Tumors are labeled as HER2-negative because they do not overexpress the HER2 protein; however, HER2-low tumors contain low levels of HER2 protein on their surface as determined by immunohistochemistry (IHC) assay and/or in situ hybridization (ISH), a technique that allows for precise localization of a specific segment of nucleic acid within a histologic section. Tumors with an IHC of +2 or +3 and gene amplification (as determined by ISH) are “HER2-positive,” while those with an IHC score of 0, +1, or +2 without gene amplification have been considered “HER2-negative.” Under the new classification, “HER2-low” tumors are those with an IHC score of +1 or +2 with negative ISH. Treatment options have traditionally been limited for this group, but in August 2022, the FDA approved Enhertu (fam-trastuzumab-deruxtecan-nxki) for the treatment of unresectable or metastatic HER2-low BC.
As the HER2-low subtype has only recently been described, much is unknown about its incidence, clinicopathologic features, or prognosis. To help address these concerns, investigators analyzed real-world data of a largest nationwide cohort to date from the Dutch Pathology Registry. Data on HER2 status (i.e., HER2-0, which included patients with a IHC score of 0 or HER2-low), estrogen receptor (ER) status, progesterone receptor (PR) status, patient clinical characteristics, histopathologic features, nodal status, reflex testing (i.e., biomarker testing using polymerase chain reaction or ISH), and overall survival (OS) were gathered from reports of primary invasive BC specimens that were obtained between January 1, 2014, and December 31, 2021, from patients aged 18 years and older who did not receive neoadjuvant treatment for BC.
Investigators identified 69,424 tumors among 65,035 patients (99.2% were women) diagnosed with invasive BC. Over two-thirds of patients had undergone breast-conserving surgery, and about one-third had had a mastectomy. Based on hormonal status, 89% were ER-positive, 8% were HER2-positive, and 4% had triple-negative BC. A discrepancy was observed in 28% of tumors for HER2 IHC scores between biopsy versus resection specimens, resulting in reclassification between HER2-low and HER2-0 categories. About 6% of patients had more than one tumor, with 37% having a different IHC score in the second tumor compared with the first tumor. Of the patients with different HER2 classifications between tumors, approximately 80% had one tumor classified as HER-0 and another classified as HER2-low.
When examining data for the 509 male patients, 93.5% were aged 50 years or older, 98.4% were ER-positive, 43% were HER2-0, 53% were HER2-low, and 5% were HER2-positive. Angioinvasion was significantly higher in HER2-low versus HER2-0 BC (16% vs. 28%, P = .008).
Clinicopathologic characteristics of HER2-0 versus HER2-low included that HER2-low tumors were associated with significantly higher expression of ER and PR, fewer high-grade tumors, more angioinvasion, slightly higher risk of recurrence, lower PR expression, and higher nodal metastases compared with HER2-0 cases. Further analysis was conducted based on ER +/- status among HER2-low patients. Having a lumpectomy, lobular, or other histology, higher ER-positive expression and lower PR expression were associated with HER2-low in the ER-positive cohort, whereas those in the ER-negative cohort with HER2-low were older (aged older than 50 years), more likely to have a lumpectomy, and to have a tumor grade 3 based on multivariant analysis.
The median follow-up time in the total study cohort was 45.9 months. Although it was initially found that HER2-low patients had a slightly longer OS compared with HER2-0 patients (93.7 vs. 92.7 months, P <.001), after adjusting for ER status there was no difference in OS between HER2-low and HER2-0 in the ER-positive or ER-negative cohorts.
Much controversy still exists regarding the legitimacy of this new classification or whether its presence is merely an artifact because current HER2 assays are designed to distinguish high from low levels of HER2 expression, not between HER2-low disease and lack of HER2 expression.
It is important for pharmacists to be aware of this new classification and its controversy as this will ultimately impact therapeutic decisions for patients with BC.
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Published March 28, 2023