Patients with HER2-Low-Positive Breast Cancer Show Promising Clinical Efficacy Signs on Antibody Drug Conjugates


With the development of anti-HER2 antibody-drug conjugates, clinicians are looking to expand the number of patients they can treat. Now, a new study shows that HER2-low-positive tumors can be identified as a new subgroup to help treat patients with HER2-positive breast cancer.

HER2-low-positive tumors can be identified as a new subgroup of breast cancer by immunohistochemistry (IHC) distinct from HER2-zero tumors in order to refine the selection of treatment for patients with therapy-resistant, hormone receptor-negative tumors, according to a study published in The Lancet.1

Looking at 2,310 tumors, researchers found that 47.5% (1,098) of the tumors were HER2-low-positive and 52.5% (1,212) were HER2-zero. Sixty-four percent (703) of patients with HER2-low-positive tumors were hormone receptor positive compared to 36.7% (445) of patients with HER2-zero tumors (P < .0001). Patients with HER2-low-positive tumors had a significantly lower pathological complete response (CR) rate than patients with HER2-zero tumors, 29.2% vs 39% respectively (P = .0002).

With the development of anti-HER2 antibody-drug conjugates, clinicians have found a new opening to develop and research new therapeutic options for patients with breast cancer who have a low expression of HER2. In a pooled analysis of individual patients, data researchers looked at 2,310 patients with HER2-non amplified primary breast cancer that had neoadjuvant combination chemotherapy in 4 different neoadjuvant trials between July 30, 2012, and March 20, 2019.

The 4 trials included GeparSepto (NCT01583426) that looked at nanoparticle-based paclitaxel vs solvent-based paclitaxel; the phase 3 GeparOcto (NCT02125344) trial, GeparX (NCT02682693) that studied the use of denosumab as an add-on to neoadjuvant treatment, and the GAIN-2 study (NCT01690702) that looked at nab-paclitaxel in high-risk patients with early breast cancer.

HER2-low-positive status was defined IHC 1+ or IHC2+/in-situ hybridisation negative and HER2-zero was defined as IHC0, based on the American Society of Clinical Oncology and College of American Pathologists guidelines. Of the patients’ data observed, disease-free survival (DFS) and overall survival (OS) data were available for 1694 patients with a median follow-up of 46.6 months.

When comparing patients with HER2-low positive tumors to patients with HER2-zero tumors they found patients with HER2-low-positive tumors had significantly longer survival data with a 3-year DFS rate of 83.4% (95% CI, 80.5%–85.9%) vs 76.1% (95% CI, 72.9%–79%). Three-year OS was also higher in patients with HER2-low positive tumors with 91.6% (95% CI, 84.9%-93.4%) compared to 85.8% (95% CI, 83%-78%) in the HER2-zero group.

Similar survival differences were also seen in patients with hormone receptor-negative tumors with 3-year DFS of 84.5% (95% CI, 79.5%–88.3%] vs 74.4% (95% CI, 70.2%–78%) and a 3-year OS of 90.2% (95% CI, 86%–93.2%] vs 84.3% (95% CI, 80.7%–87.3%). However, patients with hormone receptor-positive tumors did not have those differences with 3-year DFS of 82.8% (95% CI, 79.1%–85.9%) vs 79.3% (95% CI, 73.9–83.7), and a 3-year OS of 92.3% (95% CI, 89.6%–94.4%] vs 88.4% (95% CI, 83.8%–91.8%).

Researchers have previously written that access to anti-HER2 agents has been limited to patients with just HER2-positive tumors. However, studies like this display that the promising activity of antibody drug conjugates in patients with HER2-low positive expression allows for the effective treatment of more patients in this population.2

“HER2-low-positive tumors have a specific biology and show differences in response to therapy and prognosis, which is particularly relevant in therapy-resistant, hormone receptor-negative tumors,” the researchers wrote in the study. “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.”


  1. Denkert C, Seither F, Schneeweiss A, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021 Aug;22(8):1151-1161. doi: 10.1016/S1470-2045(21)00301-6
  2. Dieci MV, Miglietta F. HER2: a never ending story. Lancet Oncol. 2021 Aug;22(8):1051-1052. doi: 10.1016/S1470-2045(21)00349-1
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