A new treatment is effective for advanced HER2-low breast cancer

Researchers from the Hospital Clínic-IDIBAPS, the Catalan Institute of Oncology (ICO)-IDIBELL and the Vall d’Hebron Institute of Oncology (VHIO), which forms part of the Vall d’Hebron Campus, participated in an international study that shows the effectiveness of a new drug to treat HER2-low metastatic breast cancer. The treatment managed to double progression-free survival in patients with this type of cancer, compared with standard treatments.

The article, published in the New England Journal of Medicine (NEJM) includes the participation of Aleix Prat, oncologist at the Hospital Clínic, head of the IDIBAPS Translational genomics and targeted therapies in solid tumours research group, and professor at the University of Barcelona (UB); Maria Vidal, oncologist, professor and researcher in the same Hospital Clínic-IDIBAPS-UB group; Cristina Saura, oncologist and head of the Vall d’Hebron University Hospital Breast Cancer Unit and the breast cancer research group at the Vall d’Hebron Institute of Oncology (VHIO); and Miguel Gil, oncologist and head of the Medical Oncology Service at the ICO l’Hospitalet and researcher at theBellvitge Biomedical Research Institute (IDIBELL). The results will be presented this Sunday during the plenary session of the American Society of Clinical Oncology (ASCO) Annual Meeting.

Breast cancer is the most common cancer diagnosed in women worldwide, affecting 2.3 million women and killing 571,000 each year. The molecular classification of breast cancer makes it possible to decide on the best treatment according to the characteristics of the tumour. Among the different subtypes, HER2-negative breast cancers account for 70% of all breast cancer cases.

The status of HER2, a protein found on the cancer cells, is routinely determined in order to decide which treatment strategy to adopt in each case. In the case of HER2-negative metastatic tumours, it has been seen that 55% lack HER2 gene amplification (therefore, until now they were considered to be HER2-negative), but 70% of those tumours show a low-level expression of HER2 (HER2-low, defined as “1+” or “2+”). These HER2-low cancers are a very heterogeneous group, which includes two more subtypes depending on whether or not the cancer cells express hormone receptors (HR): hormone receptor (HR)-positive or hormone receptor (HR)-negative.

“Until now, patients with HER2-negative cancer did not benefit from treatments for HER2 such as trastuzumab, an antibody that has changed the prognosis of HER2-positive breast cancer”, explains Aleix Prat, member of the steering committee responsible for the clinical trial. “Now, thanks to this new immunoconjugated drug, which combines 7-8 molecules of a very potent chemotherapy with the trastuzumab antibody, patient survival is increased”, he adds.

Trastuzumab deruxtecan is a new drug that conjugates a monoclonal antibody (trastuzumab) with a chemotherapy drug (deruxtecan) and it was recently approved by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of HER2+ metastatic breast cancer. Now, this drug can target tumour cells that express low levels of HER2 and allow the cytotoxic payload to diffuse into these cells and also into adjacent cells that do not express HER2. This is known as a bystander effect. “One of the current challenges will be to ensure that HER2 levels are monitored properly. Up to now, that was not very important, but it is now, and previous studies show a great discrepancy between pathologists in the identification of low levels of HER2”, explains Maria Vidal.

The study published in the NEJM assessed the use of this drug compared with the specialist’s treatment of choice in patients with HER2-low breast cancer who had undergone one or two previous cycles of chemotherapy in addition to hormone therapy. A total of 557 patients took part in this study, 90% of whom had an HR-positive tumour and 10% had an HR-negative tumour.

Progression-free survival was approximately 10 months in patients treated with trastuzumab deruxtecan compared to 5.1 months with the usual chemotherapy. The median overall survival was 23.4 months compared with almost 17 months for the same comparison. “The results obtained are statistically significant, clinically very important, and with very manageable side effects.This treatment will soon become standard, and we hope it will not be long before it can be incorporated into the public health system, once it has been approved by the European Medicines Agency and the Spanish Agency of Medicines and Medical Devices”, says Miguel Gil.

Thus, the study concludes that treatment with trastuzumab deruxtecan is the first HER2-directed therapy to show significant clinical benefits in patients with HER2-low metastatic breast cancer. “This drug continues to be evaluated in more phase 3 clinical trials, open at our centres, in earlier stages of the disease, with patients who have not yet received chemotherapy for their metastatic tumours, to see if it improves the efficacy even more, as well as in patients with tumours that have a minimal expression of HER2 and were not included in this first study”, concludes Cristina Saura.

Image: From left to right, Maria Vidal, Miguel Gil, Cristina Saura and Aleix Prat, co-authors of the study (Photo: Francisco Avia)

Study reference:

Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer
Shanu Modi, William Jacot, Toshinari Yamashita, Joohyuk Sohn, Maria Vidal, Eriko Tokunaga, Junji Tsurutani, Naoto T. Ueno, Aleix Prat, Yee Soo Chae, Keun Seok Lee, Naoki Niikura, Yeon Hee Park, Binghe Xu, Xiaojia Wang, Miguel Gil-Gil, Wei Li, Jean-Yves Pierga, Seock-Ah Im, Halle C.F. Moore, Hope S. Rugo, Rinat Yerushalmi, Flora Zagouri, Andrea Gombos, Sung-Bae Kim, Qiang Liu, Ting Luo, Cristina Saura, Peter Schmid, Tao Sun, Dhiraj Gambhire, Lotus Yung, Yibin Wang, Jasmeet Singh, Patrik Vitazka, Gerold Meinhardt, Nadia Harbeck, and David A. Cameron.
NEJM. June 5, 2022. DOI: 10.1056/NEJMoa2203690