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

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.”

_References

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}