HER2-Positive Breast Cancer Treatment Advances in First-Line and Neoadjuvant Settings

Human epidermal growth factor receptor 2 (HER2)–positive breast cancers make up 15% to 20% of all breast tumors. In this subtype, the HER2 protein, which helps cancer cells grow, is found at unusually high levels on tumor cells. As a result, HER2-positive cancers usually grow faster than HER2-negative ones. However, because drugs specifically targeting the HER2 protein are available, these cancers often respond better to treatment than HER2-negative cancers.

A phase 3 clinical trial recently published in the New England Journal of Medicine examined trastuzumab deruxtecan (TD) as a first treatment for HER2-positive breast cancer. Trastuzumab deruxtecan is an antibody-drug conjugate (ADC), meaning it combines a molecule that attaches to HER2 proteins with a cancer-killing drug. This approach delivers the treatment directly to the tumor, where it can destroy cancer cells.

The study divided participants into three groups. One group received TD with pertuzumab, another drug that targets HER2. The second group got TD with a placebo. The third group received a combination of taxane chemotherapy, trastuzumab, and pertuzumab (THP), which is the current standard treatment for HER2-positive breast cancer.

According to an interim analysis of the study (NCT04784715), women who received TD plus pertuzumab (383 patients) had a median progression-free survival of 40.7 months, compared to 26.9 months for those who received THP (387 patients). The response rate was about 6% higher for the TD plus pertuzumab group, and the complete response rate was nearly 7% higher. The rate of serious side effects was similar in both groups.

In the neoadjuvant setting, the phase 2 TRAIN-3 trial demonstrated that the duration of chemotherapy can be individualized by using breast MRI to identify radiological complete responders. The single arm Dutch study, published in The Lancet Oncology, enrolled 467 patients with stage II–III HER2-positive breast cancer between April 2019 and May 2021.

About half the patients had hormone receptor-negative versus hormone receptor-positive tumours; most patients (87%) were clinical stage T2–T3 and 60% had lymph node involvement. The mean age of the overall group was 51 years and just under half (45%) were postmenopausal.

Contrast-enhanced breast MRI was repeated every three cycles of neoadjuvant therapy to assess treatment response. Patients had either breast-conserving surgery or mastectomy if they had an early complete radiological response (defined as the absence of pathological contrast enhancement in the original tumour region) or after completing a maximum of nine chemotherapy cycles.

The study found patients referred to surgery after only 1-3 cycles had 3-year event-free survival rates of 96·1% in the hormone receptor-negative group and 98·6% in the hormone receptor-positive group, compared with 90·6% and 85·4%, respectively, among those receiving 7-9 cycles.

The approach offers reduced treatment-related toxicity without compromising clinical efficacy. Most adverse events reported during the treatment period occurred during neoadjuvant chemotherapy, with the incidence of grade 3–4 adverse events increasing with the number of neoadjuvant chemotherapy cycles. Treatment-related serious adverse events occurred in 17 (11%) of 160 patients who received one to three cycles, 18 (12%) of 149 patients who received four to six cycles and in 21 (13%) of 158 patients who received seven to nine cycles of neoadjuvant chemotherapy.

Similarly, the incidence of neuropathy increased with the number of treatment cycles – 13% with 1-3 cycles, 35% with 4-6 cycles and 51% with 7-9 cycles. The study noted that one in three patients with hormone receptor-negative disease and one in six patients with hormone receptor-positive disease could effectively be treated with a shortened neoadjuvant regimen based on breast MRI findings without compromising efficacy.

The TRAIN-3 study was funded by Roche Netherlands.