Two experts agree Verzenio increases chances of cure for women with high risk of early breast cancer

Breast cancer treatment has come a long way in recent years, with steadily improving survival rates for patients with early-stage breast cancer and a shift in the treatment paradigm toward moving beyond survival to the goal of cure.

However, some patients with early-stage breast cancer still face a high risk of recurrence, and there is an urgent need for improved treatment strategies. That's why CDK4/6 inhibitors, which have been used to treat metastatic breast cancer, have recently gained traction.

CDK4/6 inhibitors have reduced the risk of recurrence and improved cure rates when combined with adjuvant endocrine therapy in early-stage breast cancer.

Against this backdrop, Korea Biomedical Review arranged a conversation between Valentina Guarneri, Professor Oncology at the University of Padua, Italy, and Professor Im Seock-ah of the Department of Hematology-Oncology at Seoul National University Hospital to share the latest treatment strategies for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) early breast cancer, with a focus on CDK4/6 inhibitors, and compare the Korean treatment landscape with Europe and discussed areas for improvement.

The conversation occurred during Professor Guarneri's visit to Korea last November for the 2024 American Cancer Society-Korean Cancer Society International Conference (AACR-KCA).

‘Korea's breast cancer screening program is one of the best in Asia’

Breast cancer is one of the most common cancers in women. If detected early and treated appropriately, survival rates are high. However, there are huge differences in prevalence and access to treatment between countries.

Professor Guarneri explained that in Italy, around 55,000 new cases of breast cancer are diagnosed annually. Thanks to a widespread national screening program, the majority of breast cancer cases are diagnosed in stages 1 or 2, with relatively few cases diagnosed in stages 3 or 4, she added.

“European countries are known for having a relatively high median age of breast cancer diagnosis, around 60 years, compared to Asia,” Guarneri said. “Several Italian hospitals and those in other countries are reporting a decrease in the age at diagnosis of breast cancer, which is relatively high compared to Asia. The reasons for this are speculated to be environmental or hormonal, but nothing is known.”

The situation is similar in Korea.

Professor Im noted that in Korea, early-stage breast cancer patients, which are stages 1 and 2, account for 70 percent of the total, and the remaining 30 percent are stages 3 and 4, adding that a significant number of patients are detected and diagnosed through screening tests.

“Korea offers national health examination breast cancer screening at the age of 40, which is relatively early compared to other countries,” Im said. “Few Asian countries offer routine breast cancer screening every two years for women over 40 like Korea does.”

Asian patients often have “dense breasts,” which can make it difficult for tumors to be seen on mammograms, Professor Im said. Breast ultrasound technology has been well developed in Korea, and the national screening program recommends breast ultrasound for those with dense breasts, so early detection (considering patient characteristics) is being done well, she added.

“While the peak median age of breast cancer diagnosis in Europe or the West is around 60 to 80 years old, it is lower in Korea, in the late 40s to 50s,” she said. “We speculate this may be because Korean women in this age group have as advanced life necessities lifestyles as in the West.”

‘Lack of awareness of metastasis and recurrence risk lead to delays in reimbursement’

The two experts agreed that while survival rates for early breast cancer patients are improving, some patients still face a high risk of recurrence.

“Treatment strategies and outcomes for early breast cancer have progressively evolved over the past two decades, and in recent years, personalized medicine has become more feasible,” said Dr. Guarneri. “Genomic analysis allows us to ‘de-escalate’ patients who do not need chemotherapy. For high-risk patients, we apply ‘escalation’ therapy to minimize the chance of recurrence through more intensive treatment.”

Professor Im explained that Korean healthcare providers and patients perceive the five-year survival rate for breast cancer as high as 90 percent. However, while the five-year survival rate for stage 1 breast cancer patients is close to 96 percent, the actual five-year survival rate for stage 3 patients is as low as 75 percent, indicating a gap between the perception and reality of breast cancer prognosis.

“Adjuvant treatment with ovarian function inhibitors or aromatase inhibitors has only recently been reimbursed,” Im pointed out. “The delay in insurance coverage of postoperative adjuvant therapy for early-stage breast cancer patients is also due to a lack of consideration of the risk of metastasis and recurrence of breast cancer.”

In practice, Korean patients often think that if they are stage 2B or stage 3 and HR+/HER2-, they can skip chemotherapy (because they have a good prognosis), Im explained. Some patients think that endocrine therapy is sufficient because they have 1-3 lymph node metastases. However, some of these patients do not survive beyond two to three years after surgery, when the risk of recurrence is highest.

“Even if the staging is low, if there is low ER+ expression, high grade (or grade 3) tumor grade, high proliferation index, or large tumor size, it is difficult to determine the risk-benefit ratio, but the principle is to proceed with chemotherapy and continue with adjuvant endocrine therapy,” she said, emphasizing the need for efforts to prevent recurrence in high-risk patients.

CDK4/6 inhibitors offer new promise for early breast cancer treatment

Recently, CDK4/6 inhibitors have changed the treatment paradigm by helping to increase the chances of cure in HR+/HER2- early breast cancer patients at high risk of recurrence.

Notably, Verzenio (abemaciclib) has garnered attention in Korea as the first CDK4/6 inhibitor to be approved as an adjuvant treatment for patients at high risk of lymph node-positive recurrence combined with endocrine therapy.

In the monarchE trial, Verzenio consistently maintained an invasive disease-free survival and distant relapse-free survival advantage over the control arm (endocrine therapy alone) at five years of follow-up after two years in combination with endocrine therapy, suggesting that the benefits of Verzenio treatment may be maintained over the long term, even after drug discontinuation.

“Many of the patients in the monarchE trial were those who had already received chemotherapy, so this is very important to the discussion about aggressively pursuing all available treatments,” Professor Im said.

“If you look at the actual monarchE data or the Korean patient data, the five-year invasive disease-free survival (IDFS) is about 75 percent in the high-risk, hormone receptor-positive (HR+), lymph node-positive population,” she said. “The possibility of recurrence significantly impacts patients, so it is important to treat aggressively to ensure disease-free survival at five years.”

In Korea, however, insurance does not cover adjuvant therapy with Verzenio, putting a heavy financial burden on patients. At the end of last year, the Health Insurance Review and Assessment Service (HIRA) established the “Rules for review on whether to allow benefits of existing drugs in combination with newly licensed high-priced drugs,” and Verzenio (full out-of-pocket payment by patients) was applied as the first case. This has made it easier to use the drug, but the high cost is still a significant barrier to access to treatment.

Because Verzenio is not yet covered by insurance, patients often have to consult about their financial situation before deciding on a prescription, Im explained. In real-world practice, about one in three patients who meet the indications for Verzenio adjuvant therapy are receiving Verzenio treatment out-of-pocket, she added.

“In high-risk patients, especially those with a very high risk of recurrence, the decision to proceed with Verzenio is often made,” Im said. However, many patients do not. “For example, if a patient has one lymph node metastasis with a tumor size of 5.2 centimeters and has completed all chemotherapy, she can’t help but worry. In this case, we show them the monarchE 5-year IDFS graph and explain to them that the gap with the control group is getting wider and wider, and that they can reduce the risk of recurrence and death by about 33 percent. We explain that at this point, it's important to get rid of the micrometastases and move toward a cure.”

Verzenio adjuvant therapy is free in Italy. How about Korea?

In contrast, early breast cancer patients in Italy who are at high risk of recurrence can use Verzenio for free. According to Professor Guarneri, Italian patients who meet the clinical criteria for high-risk patients in the Verzenio monarchE cohort 1 clinical trial—four or more lymph node metastases, or between one and three lymph node metastases, with a tumor size of five centimeters or more or a high tumor grade—are eligible to receive the treatment free of charge, covered by their health insurance.

“At the time of the discussion (about reimbursement for Verzenio), Italian doctors said, ‘Its use in the adjuvant setting is all about keeping patients from relapsing, and we need to keep them from getting to the stage of metastatic cancer and increase the number of patients who reach remission,’ to the insurance authorities,” Guarneri said. “From a reimbursement perspective, the insurance authorities might think that since it's approved for metastatic cancer, it can be used later after metastasis. From a physician's perspective, however, we emphasized the approach that we need to use upfront to stop recurrence earlier and increase the number of patients who reach a cure.”

“Some breast cancer patients have a poor prognosis. It's important to give them all the treatment options available, and if there is data that shows we can get them as close to a cure as possible, we should take it,” Guarneri added.

The situation in Korea is different.

In Korea, even if a new drug is developed and licensed as adjuvant therapy, it is difficult to properly evaluate the economic impact of the indication for early breast cancer because the reimbursement criteria are “overall survival (OS),” according to Professor Im. She pointed out that if a drug is used to control recurrence in early breast cancer, it may not progress to metastatic cancer, and it can reduce costs at the metastatic stage, which is very difficult to reflect in the economic evaluation.

“Korean healthcare providers have also repeatedly emphasized the importance of cure to insurance authorities, convincing them that it is important to maintain a metastasis-free situation as healthy survivors and to increase the number of patients who are cured without recurrence, especially since many of these patients are women in their 40s and 50s who are active in society and are the mainstay of their families,” Im explained.

‘Verzenio increases chances of curing early-stage breast cancer, giving hope for Korean patients, too’

“The significance of adjuvant therapy with Verzenio is that we have a new treatment strategy that can reduce the risk of recurrence and death, including distant recurrence, by about 30 percent and can increase the likelihood of cure even in patients with early breast cancer who are at high risk of recurrence,” Professor Guarneri said. “Notably, Vergenio has five years of follow-up data, so the primary endpoint data are mature, and the data are getting better and better over time so that even two years of treatment is sufficient to achieve a cure.”

She noted that Italy has a strict reimbursement process for therapies, but this does not prevent patients from getting the medication they need.

“In Italy, reimbursement for therapeutic drugs is made mostly through the government, so the criteria and review process is quite strict,” Guarneri said. “Ultimately, however, we have successfully approved reimbursement so that Verzenio is available to all patients who need it.”

“In Italy, reimbursement is available for treatments recommended by guidelines from prestigious societies, including the European Society of Medical Oncology (ESMO) and the American Society of Clinical Oncology (ASCO),” she said. “In most other countries, too, once compelling data are identified, reimbursement reviews are initiated quickly and with positive outcomes. We look forward to helping Korean patients gain access to Verzenio as soon as possible.”