With the arrival of the Antibody-Drug Conjugate (ADC) anticancer drug Enhertu (ingredient name trastuzumab deruxtecan), treatment strategies for stage 4 breast cancer are changing.
For patients with stage 4 breast cancer whose cancer has spread to other organs, existing chemotherapy often did not work, leaving limited treatment options. But the emergence of the new ADC drug, likened to a "missile" that precisely strikes cancer cells, has opened a path forward.
In particular, the recent expansion of the treatment scope for Enhertu, an ADC anticancer drug, in Korea is being credited with bringing changes across existing breast cancer classifications and overall treatment strategies.
Enhertu is the first ADC anticancer drug to receive approval from the U.S. Food and Drug Administration (FDA) in the breast cancer field. It was developed by the Japanese drugmaker Daiichi Sankyo and is being globally commercialized and co-marketed through an alliance with the British drugmaker AstraZeneca.
Korea Daiichi Sankyo and AstraZeneca Korea on the 19th received approval from the Ministery of Food and Drug Safety for use of Enhertu monotherapy in patients with metastatic breast cancer with HER2 (human epidermal growth factor receptor 2) low expression (IHC 1+ or IHC 2+/ISH-) and ultralow expression (IHC 0). HER2 is a protein receptor that promotes the growth and division of cancer cells.
Its indication (treatment scope) has expanded beyond metastatic HER2-positive breast and gastric cancers to include metastatic breast cancer with HER2 low and ultralow expression after endocrine therapy.
Breast cancer has been classified by the biological characteristics of the tumor into ▲ hormone receptor–positive ▲ HER2-positive ▲ triple-positive ▲ triple-negative. By patient share, hormone receptor–positive breast cancer accounts for about 70%, HER2-positive is under 20%, and triple-negative is around 10%–15%. With this expanded indication, Enhertu can be given early not only to patients who have undergone chemotherapy after endocrine therapy, but also before chemotherapy.
On Jan. 29 at Seoul St. Mary's Hospital in Seocho District, Seoul, Professor Shin Gap-soo of medical oncology said, "Stage 4 breast cancer is now becoming a manageable disease," adding, "Among stage 4 HER2-positive patients, many who receive Enhertu as first-line therapy can maintain lives in a state close to near-cure."
Through Shin, we looked at how the classification system for metastatic breast cancer and early treatment strategies have changed since Enhertu's introduction. The following is a Q&A with Shin.
– What are the age groups of breast cancer patients in Korea?
"We need to consider all adult age groups. The incidence is highest among patients in their 50s, but the proportions are also high in both older and younger groups. It is no exaggeration to say it ranges from people in their 20s to those 100 years old. In Korea, nearly 30,000 people are diagnosed with breast cancer each year, and that number continues to grow."
– With the Ministery of Food and Drug Safety's approval expanding the indication, Enhertu can now be used for patients with HER2 low and ultralow expression. What do HER2 low and ultralow expression mean?
"Breast cancer is basically classified by the tumor's biological characteristics into hormone receptor–positive, HER2-positive, and triple-negative. HER2 ultra/low expression refers to a state in which HER2 is faintly present in cancer cells. Most are hormone receptor–positive breast cancers. Among these, HER2-positive breast cancer tends to have poorer prognosis because the cancer cells' biological characteristics are aggressive."
– What were the previous treatments for HER2 low and ultralow expression breast cancer?
"Endocrine therapy is effective, but once resistance develops, chemotherapy is used. In the metastatic setting, the progression-free survival with chemotherapy was limited to about six months."
– Has Enhertu shown efficacy for these patients as well?
"Yes. In global clinical trials involving patients with HER2 low and ultralow expression, it showed clearly superior efficacy compared with conventional chemotherapy. In the DESTINY-Breast 04 clinical study of HER2 low breast cancer patients who had received at least one prior chemotherapy, the progression-free survival was about 10 months in the Enhertu arm versus about five months with other chemotherapy. In the DESTINY-Breast 06 clinical study of patients naïve to chemotherapy (including HER2 low and ultralow patients), progression-free survival was about 13 months, showing a clear difference from approximately eight months with chemotherapy."
– What is the significance of this expanded indication for Enhertu?
"With the introduction of Enhertu in clinical studies, breast cancer has been redefined based on HER2 expression. It is important to note that it consistently showed good responses regardless of mutation type in breast cancer. Although Enhertu was first developed for HER2-positive disease, clinical trials confirmed it is effective even when HER2 is not abundant. This means most breast cancer patients can see anticancer benefits with Enhertu."
– Does that mean existing treatment criteria and strategies have changed?
"That is a fair assessment. Previously, the main strategy was to target cancer cell division, but Enhertu demonstrated strong anticancer effects when the target was effectively engaged. The drug is so efficacious it has effectively created a new classification framework. Various ADC therapies are emerging, but it will likely be difficult for them to surpass the Enhertu benchmark for the time being."
– Have strategies changed in real-world clinical settings as well?
"Yes. Based on the DESTINY-Breast 04 and 06 trials, these are being applied in clinical practice worldwide. In Korea, since January, more patients have been able to receive Enhertu following the expanded indication."
– I am also curious about cases showing the benefits of early administration.
"Enhertu is effective but has toxicities. A representative adverse event is interstitial lung disease (ILD), which appears in about 1 in 10 patients. With early detection and proper management, most can be re-treated. Nausea and vomiting are manageable as well. The adverse events are surmountable, and the benefits and strengths are superior."
– How is HER2 ultralow expression tested?
HER2 expression is assessed in solid tumor tissue. HER2-positive, HER2 low, HER2 ultralow, and HER2 negative (Null) are all based on tissue testing criteria. Upon metastasis, a tissue biopsy should be performed to confirm HER2 ultralow expression. If tissue access is difficult, previous surgical specimens can be used.
– Can it also be confirmed with a liquid biopsy?
"For now, it is an adjunctive method. The standard is to confirm in solid tumor tissue, and liquid biopsy has limitations."
– What are the differences between domestic and international guidelines?
"HER2-positive and low expression are tested according to the American Society of Clinical Oncology (ASCO)–College of American Pathologists (CAP) guidelines. HER2 ultralow expression is not yet fully systematized, but the FDA approved it based on DESTINY-Breast 06, and ASCO is accepting it. It is applied in Korean clinical practice as well."
– What issues need to be addressed institutionally in Korea?
"Enhertu received approval relatively quickly in Korea, but if a drug is excellent, faster adoption is needed. To achieve that, not only clinicians but also institutional and administrative communication are important."
– What would you like to say to breast cancer patients?
"Ten to twenty years ago, stage 4 cancer was an 'incurable area,' but now the phrasing has shifted from 'cannot be cured' to 'difficult to cure.' Among patients with stage 4 breast cancer, a fairly high proportion of those with HER2-positive disease show courses akin to cure. While we cannot use the term cure lightly, after first-line Enhertu, some can maintain lives in a state close to near-cure. Diagnosis and treatments continue to advance. I hope patients do not lose hope and continue treatment."