Editor's Note: The 21st Shanghai International Breast Cancer Symposium (SIBCS) was held in Shanghai on October 16–17, 2026. The meeting brought together experts in breast cancer from across China for in-depth discussions on comprehensive breast cancer management and precision, stratified treatment.In HR+/HER2− advanced breast cancer, the widespread use of CDK4/6 inhibitors in early-stage adjuvant therapy has increased the number of patients developing resistance and raised new clinical challenges. At the conference, Oncology Frontier interviewed Professor Jian Zhang of Fudan University Shanghai Cancer Center about treatment stratification for these patients and the clinical value of next-generation CDK inhibitors.
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Oncology Frontier: As CDK4/6 inhibitors are increasingly incorporated into adjuvant treatment for high-risk early breast cancer, more patients are experiencing recurrence and subsequently entering the first-line advanced-disease setting. For patients with HR+/HER2− breast cancer who have already received adjuvant CDK4/6 inhibition, how should clinicians approach treatment selection when the disease recurs?
Professor Jian Zhang: In recent years, CDK4/6 inhibitors have been incorporated into adjuvant treatment intensification strategies for high-risk early breast cancer, and some patients do experience recurrence after completing adjuvant therapy. An important consideration is that most pivotal phase III trials of traditional first-line treatment for advanced disease excluded patients who had previously received CDK4/6 inhibitors in the adjuvant setting. Therefore, the traditional first-line treatment experience cannot simply be extrapolated to this population.
Clinical decisions should take several factors into account, including the interval between recurrence and previous treatment, molecular testing results, and the presence or absence of visceral crisis.
First, the interval to recurrence is a key consideration. If recurrence occurs more than 12 months after completion of adjuvant CDK4/6 inhibitor therapy, and the tumor remains estrogen receptor (ER)-positive without visceral crisis, CDK4/6 inhibitor therapy may be considered again in accordance with expert consensus. In practice, however, switching to a different CDK4/6 inhibitor is generally recommended, alongside adjustment of the endocrine therapy backbone, following the principles used in first-line advanced-disease management.
It is important to distinguish between two timelines: the time at which adjuvant endocrine therapy ends and the time at which adjuvant CDK4/6 inhibitor treatment ends. These two dates do not necessarily coincide.
Conversely, recurrence during CDK4/6 inhibitor treatment or shortly after its discontinuation often suggests that the tumor has already developed resistance in the early stages of treatment and that the overall risk is higher. In such cases, clinicians should not automatically adopt a conventional first-line regimen. Instead, treatment should follow the principles used in the second-line setting, with comprehensive testing for alterations in genes such as ESR1, PIK3CA, AKT/PTEN, and BRCA. If visceral crisis is present, chemotherapy should be prioritized.
Second, dynamic molecular monitoring is valuable. If an ESR1 mutation is detected but imaging shows no disease progression, clinicians may consider switching the existing aromatase inhibitor to a selective estrogen receptor degrader (SERD), such as an oral SERD or fulvestrant, while retaining CDK4/6 inhibition. The PADA-1 and SERENA-6 studies have both demonstrated that this early-switch strategy can significantly prolong progression-free survival (PFS). For patients with PIK3CA mutations, several phase III studies evaluating combinations of PI3K/AKT/mTOR pathway inhibitors and CDK4/6 inhibitors are ongoing and warrant attention.
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Oncology Frontier: In the second-line setting for HR+/HER2− advanced breast cancer, many patients have already received CDK4/6 inhibitors. What treatment options are currently available for these patients? How should clinicians choose a treatment strategy for those without clearly actionable genomic alterations?
Professor Jian Zhang: By the time patients enter the second-line setting, their disease has progressed following CDK4/6 inhibitor treatment, PFS is often substantially shorter, and the mechanisms of drug resistance are more complex.
When making treatment decisions, I generally begin by clarifying two key questions. First, has testing identified any actionable genomic alterations? Second, is the patient still suitable for endocrine-based therapy? Once these questions have been answered, the treatment direction becomes much clearer.
Available options include rechallenge with a conventional CDK4/6 inhibitor, use of a newer CDK inhibitor, an oral SERD alone or in combination with a CDK inhibitor, and endocrine therapy combined with agents targeting the PI3K/AKT/mTOR pathway. If the disease is no longer suitable for endocrine therapy, treatment should be switched promptly to an antibody-drug conjugate (ADC) or chemotherapy.
However, for patients without actionable alterations such as ESR1, PIK3CA, or AKT/PTEN mutations who remain suitable for endocrine therapy, current treatment options have significant limitations.
Clinical trial results for rechallenge with traditional CDK4/6 inhibitors have been inconsistent, with both positive and negative findings, and reliable biomarkers for identifying patients most likely to benefit remain lacking. For patients without ESR1 mutations, the benefits of oral SERD monotherapy are also relatively limited. Dual PI3K/mTOR inhibition has demonstrated survival benefits in some patients with wild-type PIK3CA, but metabolic and gastrointestinal adverse events require close management.
If patients develop visceral crisis or experience rapid tumor progression and are no longer suitable for endocrine therapy, chemotherapy or an ADC should be considered as a priority.
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Oncology Frontier: What clinical value do next-generation CDK inhibitors, exemplified by CDK2/4/6 inhibitors, offer within the current treatment landscape for HR+/HER2− advanced breast cancer?
Professor Jian Zhang: Traditional CDK4/6 inhibitors have undoubtedly formed the foundation of endocrine-based combination therapy for HR+/HER2− advanced breast cancer. However, acquired resistance remains common in clinical practice. One important mechanism involves upregulation of the Cyclin E–CDK2 pathway, through which tumor cells bypass CDK4/6 inhibition and sustain cell-cycle progression.
Next-generation CDK inhibitors primarily include dual CDK2/4/6 inhibitors and highly selective CDK4 inhibitors. These agents offer new approaches to treatment by targeting resistance mechanisms and potentially improving the balance between efficacy and safety.
Take lerociclib as an example. It is a CDK2/4/6 inhibitor. In the phase III CULMINATE-2 study in the first-line advanced-disease setting, lerociclib combined with an aromatase inhibitor significantly reduced the risk of disease progression. A phase II study also observed encouraging antitumor activity in patients whose disease had become resistant to previous CDK4/6 inhibitor therapy, providing an additional treatment option for this high-risk population.
From a safety perspective, CDK6 is highly expressed in hematopoietic cells, and CDK6 inhibition is an important contributor to the reduction in neutrophil counts. Lerociclib’s differentiated inhibition of CDK6 may therefore reduce the incidence of moderate-to-severe neutropenia, potentially making long-term treatment more manageable.
In addition to CDK2/4/6 inhibitors, the highly selective CDK4 inhibitor atirmociclib is also worth watching. It preferentially inhibits CDK4 while reducing the intensity of CDK6 inhibition, with the aim of mitigating the risk of bone marrow suppression. The phase II FOURLIGHT-1 study has demonstrated a reduced risk of disease progression in patients previously exposed to CDK4/6 inhibitors, and the corresponding phase III FOURLIGHT-3 study is underway.
Overall, next-generation CDK inhibitors are not simply intended to replace conventional CDK4/6 inhibitors. Rather, they expand the treatment options available for stratified management of HR+/HER2− advanced breast cancer, particularly in settings where existing therapies do not fully meet clinical needs. These include patients at high risk of resistance to first-line treatment, those whose disease recurs after adjuvant CDK4/6 inhibitor therapy, and those without actionable genomic alterations following progression. Nevertheless, some clinical data remain preliminary. In practice, treatment decisions must continue to weigh each patient’s recurrence pattern, molecular testing results, and treatment tolerability.
