medwireNews: Breast tumors with low levels of HER2 expression represent a defined subtype of breast cancer with specific biology, responses to therapy, and prognosis, German research suggests.
Writing in The Lancet Oncology, Carsten Denkert (Philipps-Universität Marburg) and co-authors say their “results provide a basis for a better understanding of the biology of breast cancer subtypes and the refinement of future diagnostic and therapeutic strategies.”
In their pooled analysis of data for 2310 patients with HER2-non-amplified primary breast cancer from the prospective GeparSepto, GeparOcto, GeparX, and Gain-2 neoadjuvant clinical trials, 47.5% of tumors were HER2-low (immunohistochemistry [IHC] 1+ or IHC2+ with negative in-situ hybridization) and 52.5% were HER2-negative (HER2-zero IHC0).
A significantly higher proportion of HER2-low versus HER2-zero tumors were hormone receptor (HR)-positive, at 64.0% versus 36.7%. In addition, HER2-low tumors had a lower proliferation rate (median Ki-67, 40.0 vs 51.5) and were less likely to be grade III (59.8 vs 72.2%) than HER2-zero tumors.
The pathologic complete response rates (pCRs) among the participants, who all received either conventionally scheduled or intensified dosedense anthracycline–taxane-based chemotherapy, were significantly lower for HER2-low tumors than for HER2-zero ones, at 29.2% versus 39.0%, but the responses also varied by HR status.
Specifically, pCRs were significantly lower for HER2-low versus HER2-zero tumors that were HR-positive (17.5 vs 23.6%), but there was no significant difference by HER2 status when tumors were HR-negative (50.1 vs 48.0%).
Despite lower pCR rates, the researchers found that 3-year disease-free survival (DFS) rates were significantly higher in the HER2-low group than in the HER2-zero group, at 83.4% versus 76.1%.
However, in this case there was no significant difference by HER2 status for HR-positive tumors (82.8 vs 79.3%), but there was when the tumors were HR-negative, with the 3-year DFS rate significantly higher in the HER2-low group than in the HER2-zero group (84.5 vs 74.4%).
The pattern was similar for overall survival (OS), where the 3-year rate was 91.6% in people with HER2-low tumors and 85.8% in those with HER2-zero tumors, a significant difference.
For HR-positive individuals, 3-year OS was 92.3% with HER2-low tumors and 88.4% with HER2-zero tumors, while for HR-negative tumors the corresponding rates were 90.2% and 84.3%, with differences only significant in the HR-negative group.
Denkert and team conclude that “HER2-low-positive tumours can be identified as [a] new subgroup of breast cancer by standardised IHC, distinct from HER2-zero tumours.”
However, they acknowledge that “additional standardisation is needed before low HER2 expression can be used as a routine biomarker to select patients for further therapy options.”
In an accompanying comment, Maria Vittoria Dieci and Federica Miglietta, both from the University of Padova in Italy, say that “[t]he HER2-low-positive concept serves as an emblematic example in oncology, highlighting an increasing need for flexibility, thus prompting us to be open minded towards replacing the old pattern of fixed and strict categories, in favour of more blurred boundaries as our knowledge increases and treatment opportunities expand.”
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Lancet Oncol 2021; doi:10.1016/S1470-2045(21)00301-6
Lancet Oncol 2021; doi:10.1016/S1470-2045(21)00349-1