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Outcomes in Patients With HER2-Low–Positive Breast Cancer Participating in Neoadjuvant Clinical Trials


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In a pooled analysis of individual patient data from breast cancer neoadjuvant clinical trials reported in The Lancet Oncology, Carsten Denkert, MD, and colleagues found that pathologic complete response and survival rates for patients with HER2-low–positive vs HER2-zero tumors differed according to hormone receptor (HR) status.

Study Details

The study included 2,310 patients with HER2-nonamplified primary breast cancer treated with neoadjuvant combination chemotherapy in four prospective neoadjuvant clinical trials—GeparSepto, GeparOcto, GeparX, and Gain-2—between July 2012 and March 2019. Prospective central HER2 testing was performed before random assignment in all trials. HER2-low–positive status was defined as immunohistochemistry (IHC) 1+ or IHC2+/in situ hybridization–negative, and HER2-zero was defined as IHC0 based on ASCO/College of American Pathologists guidelines.


Our results show that HER2-low–positive tumors can be identified as [a] new subgroup of breast cancer by standardized IHC, distinct from HER2-zero tumours. HER2-low–positive tumors have a specific biology and show differences in response to therapy and prognosis, which is particularly relevant in therapy-resistant, HR-negative tumors.
— Carsten Denkert, MD, and colleagues

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Key Findings

Among the 2,310 patients, 1,098 (47.5%) had HER2-low–positive tumors and 1,212 (52.5%) had HER2-zero tumors. HR-positive disease was present in 703 (64.0%) of those with HER2-low–positive tumors and 445 (36.7%) of those with HER2-zero tumors (P < .0001).

Among all patients, pathologic complete response was achieved significantly less frequently in those with HER2-low–positive vs HER2-zero status (29.2% vs 39.0%, P = .0002). The pathologic complete response rate was significantly lower in HER2-low–positive vs HER2-zero patients with HR-positive disease (17.5% vs 23.6%, P = .024), but not among those with HR-negative disease (50.1% vs 48.0%, P = .21).

Disease-free and overall survival data were available for 1,694 patients (from all trials except GeparX) with a median follow-up of 46.6 months (interquartile range = 35.0–52.3 months). At 3 years, disease-free survival was 83.4% in the HER2-low–positive group vs 76.1% in the HER2-zero group (P = .0084); 3-year overall survival was 91.6% vs 85.8% (P = .0016).

Among patients with HR-negative disease, rates of 3-year disease-free survival (84.5% vs 74.4%, P = .0076) and 3-year overall survival (90.2% vs 84.3%, P = .016) were significantly greater for HER2-low–positive vs HER2-zero status.

Among patients with HR-positive disease, there were no significant differences for HER2-low–positive vs HER2-zero status in 3-year disease-free survival (82.8% vs 79.3%, P = .39) or 3-year overall survival (92.3% vs 88.4%, P = .13).

The investigators concluded, “Our results show that HER2-low–positive tumors can be identified as [a] new subgroup of breast cancer by standardized IHC, distinct from HER2-zero tumours. HER2-low–positive tumors have a specific biology and show differences in response to therapy and prognosis, which is particularly relevant in therapy-resistant, HR-negative tumors. Our results provide a basis for a better understanding of the biology of breast cancer subtypes and the refinement of future diagnostic and therapeutic strategies.”

Dr. Denkert, of the Institute of Pathologie, Philipps-Universität Marburg and University Hospital of Giessen and Marburg, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by German Cancer Aid (Deutsche Krebshilfe). For full disclosures of the study authors, visit thelancet.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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