'Breast cancer enters age of precision: a happy concern for Korean clinicians'

“In the past, oncologists used to decide which drugs to use, but now it's different. Various departments, including pathology and clinical genomics, collaborate to select the most suitable drugs. The abundance of drugs has made it possible to customize treatment for each patient, and the depth of thought has increased. I like to call it a ‘happy concern.’ However, at the same time, new challenges have arisen: how well can we apply this precise treatment approach within the Korean medical system, and to what extent can we keep up with it?” (Professor Im Seock-ah of the Department of Hematology-Oncology at Seoul National University Hospital)

At the American Society of Clinical Oncology's Annual Meeting (ASCO 2025), the world's largest cancer conference, held early last month, data from various new drugs aimed at treating breast cancer were presented. While each of the new drugs touted dazzling research achievements, what stood out was that they were all pointing in the same direction. The paradigm of “more precise, more personalized treatment.”.

According to Professor Im, who met with Korea Biomedical Review on the sidelines of ASCO 2025, the paradigm of breast cancer treatment is undergoing rapid and dramatic changes.

For instance, in the past, treatment was roughly guided by the results of a biopsy. Now, however, drugs are selected based on a combination of genes, protein expression, and response to treatment. In the name of “precision medicine,” breast cancer is no longer a single disease, but a disease with many faces.

No longer do patients receive the same treatment under the category of “hormone receptor positive.” And being “HER2-negative” doesn't exclude you from targeted therapies, or a “triple-negative” diagnosis doesn't mean you have to despair.

Genes drive treatment in hormone receptor breast cancer

“It used to be that you had to have 10 percent or more hormone receptors to be hormone receptor positive (HR+). However, with the advent of aromatase inhibitors and fulvestrant, the threshold has been lowered because only 1 percent of hormone receptors is needed to show an effect on the drug. In practice, however, the response of a patient with less than 10 percent estrogen receptor low expression (ER-low) and a patient with more than 50 percent is completely different.”

The change is possible because there are now treatment options to choose from, Professor Im said, explaining that patients who were previously “lumped together into one group” are now being separated and treated separately.

The aforementioned hormone receptor-positive (HR+/HER2-) breast cancer is the most common subtype among breast cancer patients. Still, familiarity doesn't mean simplicity, especially when genetic alterations, such as PIK3CA mutations or ESR1 mutations, are involved, which can alter the course of treatment.

“PIK3CA mutations are found in about 40 percent of hormone receptor-positive breast cancer patients, so PI3K inhibitors or AKT inhibitors that block this pathway have become very important,” she said.

Professor Im emphasized that if PIK3CA mutations are detected early and targeted therapies are used appropriately, the prognosis for patients can be completely different. Given the distinctly different biology of cancers, this one gene can determine not only the direction of treatment but also the length of survival.

The INAVO120 clinical data presented at ASCO 2025 clearly illustrate this trend. Inavolisib is an oral targeted therapy selective for PI3Kα, and the INAVO120 study is a global phase 3 trial in metastatic hormone receptor-positive (HR+/HER2-) breast cancer patients with PIK3CA mutations. Patients received palbociclib and fulvestrant as a standard of care in the absence of prior CDK4/6 inhibitor therapy, followed by either inavolisib or placebo.

The data presented here are the final results for overall survival (OS), which was 34 months in the inavolisib arm, seven months longer than the 27 months in the placebo arm. In addition, based on previously announced primary endpoint results, median progression-free survival (PFS) in the inavolisib combination arm was 17.2 months, more than double the 7.3 months in the placebo arm.

Inavolisib also demonstrated a significant safety advantage compared to the existing PI3K inhibitor, alpelisib (Piqray). While alpelisib was successful in improving progression-free survival (PFS), frequent side effects, including hyperglycemia, skin rash, and diarrhea, led to low drug adherence and limited clinical use. In contrast, inavolisib was designed to precisely target PI3Kα mutations, reducing the incidence of side effects while maintaining therapeutic efficacy, resulting in clinical advances by being the first PI3K inhibitor to demonstrate an improvement in overall survival (OS).

There is also capivasertib (trade name Truqap), which targets a different point in the same pathway. It works by directly inhibiting the AKT protein in the PI3K-AKT-mTOR pathway, a central pathway for cancer cell survival and proliferation.

In particular, the CAPItello-291 study showed that when combined with fulvestrant, it nearly doubled progression-free survival (PFS) from 3.6 months to 7.2 months and reduced the risk of cancer progression by 40 percent compared to placebo in patients who progressed after hormonal therapy.

Importantly, a significant treatment response was observed in the capivasertib arm, even though many of the patients in the study had received prior CDK4/6 inhibitor therapy. The fact that it remains effective in a resistant setting is a strong indication that this drug has potential as a next-generation targeted therapy.

Most importantly, both of these agents are the first to offer hormone receptor-positive patients a “medicine that fits my genes” approach to treatment.

Enhertu rewrites the boundaries of HER2

Breast cancer tends to be more aggressive when there is more of the HER2 protein. Ironically, however, patients with high HER2 expression have been able to benefit from effective therapies because they have a clear target. On the other hand, patients with ambiguous or low HER2 expression have long been categorized as “untargeted”.

However, that landscape completely changed. Now, even a “little bit” of HER2 is treatable. And at the center of this change is Enhertu (trastuzumab deruxtecan).

As a game-changer for HER2-positive breast cancer, it has begun to reshape the treatment paradigm, most notably in the DESTINY-Breast04 study, which opened the door to targeted therapy for HER2-low patients who were previously classified as HER2-negative, i.e., IHC 1+ or 2+ but FISH-negative, and dramatically expanded their treatment options. Patients who were previously excluded from treatment opportunities because their HER2 was not clearly “high” can now experience the benefits of targeted therapy firsthand.

Beyond its success in patients with low HER2 expression, Enhertu has also shown clinical benefit in the ultra-low expression (HER2-ultralow, IHC between 0 and 10 percent) patient population, where HER2 expression is almost non-existent, posing new challenges. Quantifying and subdividing HER2 expression is opening the door to treating patients in the “gray zone” who previously appeared to be helpless, thus increasing the role of pathology.

Because subtle differences in HER2 expression can mean the difference between a viable treatment or not, pathologists are working hard to make precise distinctions and standardize diagnostic criteria.

“Unlike the West, which has traditionally practiced FISH-based classification, Korea has long been using IHC to categorize HER2-low into 0, 1+, 2+, and 3+, so we are relatively familiar with diagnosing HER2-low. However, it is now important to accurately distinguish HER2-ultralow from IHC 0, so the pathology department is promoting standardization through various workshops and trainings," Professor Im said.

Im emphasized that multidisciplinary collaboration to define and translate this fine line into clinical practice will become even more important in the future.

Most importantly, she noted that even if a patient has HER2 of “0,” there is now a treatment option called Trodelvy (sacituzumab govitecan), which opens up new possibilities for patients who have long been left behind.

Patients who were previously excluded from targeted therapies because they had a HER2 level of “0” can now be brought back into the treatment strategy.

Trodelvy surmounts the triple-negative breast cancer barrier

Trodelvy’s innovation extends further. The ASCENT-04/KEYNOTE-D19 study, presented at ASCO 2025, clearly demonstrated that Trodelvy can go beyond existing treatment strategies as a first-line treatment for PD-L1-positive metastatic triple-negative breast cancer (TNBC).

The current standard of care in this patient population is a combination of taxane-based chemotherapy and the immune checkpoint inhibitor pembrolizumab (Keytruda). However, this treatment has been limited by its inability to substantially extend survival and its frequent quality of life impairment due to paresthesia and edema.

The ASCENT-04 study aimed to address this limitation. Patients in the Trodelvy plus pembrolizumab arm had a significantly longer median progression-free survival (PFS) (11.2 months vs. 7.8 months) and a 35% reduction in the risk of disease progression compared to the conventional chemotherapy arm. The duration of response was also significantly improved compared to the control group, and most notably, the treatment was more sustainable due to a different pattern of side effects.

In triple-negative breast cancer, where a cure is hard to expect, prolonging survival and maintaining quality of life during treatment are key issues. Trodelvy, an antibody-drug conjugate (ADC) targeting TROP-2, presents new possibilities as a combination partner for prolonged treatment continuation.

Most importantly, it has given new hope to patients who have long been frustrated by the notorious triple-negative breast cancer barrier.

Clinicians face a 'happy concern'

With this influx of new drugs, breast cancer no longer relies on simple classification criteria, but rather requires a biologic and molecular targeted approach.

A “precision strategy” that identifies the genetic and proteomic profile of a patient's tumor and selects the optimal drug accordingly has become essential. It requires early and accurate characterization of a patient's tumor using a variety of diagnostic and analytical technologies.

And all of these changes cannot be accomplished by a single oncologist. It requires a coordinated effort across the entire process, from diagnosis to treatment decisions. Ultimately, precision medicine is not a matter of sophisticated technology, but rather a concept that necessitates a fundamental shift in team-based collaboration. It's about thinking and acting together, not alone. And we are at the tipping point.

Professor Im’s phrase, “happy concern,” reflects both the new possibilities that precision medicine has opened up and the grim reality of our medical field.