With the arrival of the Antibody-Drug Conjugate (ADC) cancer 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 with the launch of new ADC drugs likened to a "missile that precisely strikes cancer cells," a path to treatment has opened.
In particular, the recent expansion of the treatment scope of the ADC cancer drug Enhertu in Korea is being credited with bringing changes to the overall classification and treatment strategies for breast cancer.
Enhertu is the first ADC cancer drug to win approval from the U.S. Food and Drug Administration (FDA) in the field of breast cancer. It was developed by the Japanese pharmaceutical company Daiichi Sankyo and is being globally commercialized and co-marketed through a partnership with the British pharmaceutical company AstraZeneca.
Korea Daiichi Sankyo and Korea AstraZeneca on the 19th received approval from the Ministery of Food and Drug Safety for the use of Enhertu as monotherapy in patients with HER2 (human epidermal growth factor receptor 2) low expression (IHC 1+ or IHC 2+/ISH-) and ultralow expression (IHC 0) metastatic breast cancer. HER2 is a protein receptor that promotes the growth and division of cancer cells.
The 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 administered earlier not only to patients who previously received chemotherapy after endocrine therapy, but also without chemotherapy.
On the 29th, at Seoul St. Mary's Hospital in Seocho District, Seoul, oncology professor Shin Gap-su said, "Now even stage 4 breast cancer is turning into a manageable disease," and "among stage 4 HER2-positive patients, many who receive Enhertu as first-line therapy can maintain lives in a near-cure state."
Through Professor Shin, we looked at the changed classification system for metastatic breast cancer and early treatment strategies since the introduction of Enhertu. The following is a Q&A with Professor Shin.
– What are the age groups of breast cancer patients in Korea?
"We have to consider all adult age groups. Incidence is highest among patients in their 50s, but the proportions are also high in older and younger groups. It is no exaggeration to say from the 20s to age 100. In Korea, close to 30,000 breast cancer patients are diagnosed a year, and that number keeps rising."
– With the Ministery of Food and Drug Safety's approval to expand 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 on cancer cells. Most are hormone-positive breast cancers. Among these, HER2-positive breast cancer tends to have aggressive biological characteristics and a relatively poor prognosis."
– What were the previous treatments for patients with HER2 low/ultralow expression breast cancer?
"Endocrine therapy is effective, but if resistance develops, we use chemotherapy. In the metastatic setting, progression-free survival on chemotherapy was limited to about six months."
– Did Enhertu show treatment effects in those patients as well?
"Yes. In global clinical trials targeting patients with HER2 low and ultralow expression, it showed clearly superior efficacy versus existing chemotherapy. In the DESTINY-Breast 04 clinical study of HER2 low breast cancer patients who had received one or more lines of chemotherapy, progression-free survival was about 10 months in the Enhertu arm versus about five months in the other chemotherapy arm. In the DESTINY-Breast 06 clinical study of patients not previously exposed to chemotherapy (including HER2 low and ultralow patients), progression-free survival was about 13 months, showing a clear difference compared with about eight months for chemotherapy."
– What is the significance of this expanded indication for Enhertu?
"With the introduction of Enhertu in clinical practice, breast cancer has been redefined based on HER2 expression. We should give meaningful weight to the fact that it showed consistently good responses regardless of mutation type in breast cancer. While Enhertu was first developed for HER2-positive disease, clinical trials confirmed it is effective even when HER2 is not abundant. Most breast cancer patients can now see anticancer benefits with Enhertu."
– Does this mean the previous treatment standards and strategies have changed?
"You could say that. Previously, the main strategy was to target cancer cell division, but with Enhertu we confirmed strong anticancer effects when the target was effectively engaged. The drug is so potent that it has effectively created a new classification framework. Various ADC treatments are emerging, but it will likely be difficult 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, it is being applied in clinical settings worldwide. In Korea, since January, more patients have been able to receive Enhertu following the expanded indication."
– I'm also curious about cases showing the effects of early administration.
"Clinical practice is confirming that using a more effective therapy earlier can translate into longer survival. In that sense, Enhertu can be considered at a more advanced treatment stage in Korea, where there are many young breast cancer patients who can quickly develop resistance after endocrine therapy.
Enhertu is effective but has toxicity. The representative adverse reaction is interstitial lung disease (ILD), which occurs in about 1 in 10 patients. With early detection and appropriate management, most can be re-challenged. Nausea and vomiting are also manageable. Adverse reactions are surmountable, and the benefits and efficacy are superior."
– How do you test for HER2 ultralow expression?
"HER2 expression is assessed in solid tumor tissue. HER2 positive, HER2 low, HER2 ultralow, and HER2 negative (null) are all based on tissue testing standards. At metastasis, a tissue biopsy should be performed to confirm HER2 ultralow expression. If tissue access is difficult, past surgical specimens can be used for determination."
– Can it also be confirmed with liquid biopsy?
"For now, it is a supplementary method. The standard is confirmation in solid tumor tissue, and liquid biopsy has limitations."
– What are the differences between domestic and overseas guidelines?
"HER2 positivity and low expression are tested according to 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 also accepting it. It applies to clinical practice in Korea as well."
– Are there institutional issues to address in Korea?
"Enhertu was approved relatively quickly in Korea, but if a drug is outstanding, faster introduction is needed. To achieve this, communication not only among clinicians but also at the institutional and administrative levels is important."
– What would you like to say to breast cancer patients?
"Ten to twenty years ago, stage 4 cancer was considered 'an area that cannot be cured,' but now the wording is shifting from 'cannot be cured' to 'hard to cure.' Among stage 4 breast cancer patients, the share of HER2-positive patients who show a course akin to cure is quite high. While we cannot use the word cure lightly, after first-line Enhertu, some can maintain lives in a state close to cure. Diagnosis and treatments continue to advance. I hope patients do not lose hope and continue treatment."