Factors Affecting Outcomes After Progression in Stage 4 Breast Cancer

Breast cancer is the most common cancer in women worldwide. At diagnosis, approximately 10% of patients have stage four, or metastatic disease. Among those diagnosed at earlier stages, approximately 20% eventually develop metastatic disease. HR-positive, HER2-negative tumors account for approximately 70% of breast cancers and are generally sensitive to endocrine therapy. In these patients, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, approved and introduced after 2015, includingReampla, Valamor , and Yulareb, have been highly effective and substantially extended survival. Nevertheless, resistance over time remains a major problem in stage 4 hormone-positive breast cancer.

There is no firm consensus on survival determinants or the best treatment after progression on CDK4/6 inhibitors. To address this uncertainty, a study at the European Institute of Oncology in Italy, led by Dr. Pier Paolo Maria Berton Giachetti and published on 25 February 2025 in JAMA Network Open , comprehensively assessed the effects of CDK4/6 treatment duration, metastatic disease characteristics, and chemotherapy options on survival.

Factors Affecting Outcomes After CDK4/6 Inhibitors

The study reviewed 506 patients with HR-positive, ERBB2-negative metastatic breast cancer whose disease progressed during endocrine therapy plus CDK4/6 inhibitors. The main findings were:

• CDK4/6 inhibitor treatment of longer duration (more than 12 months) was associated with better overall survival (HR: 0.55).

• Visceral (internal organ) metastases affected overall survival adversely (HR: 1.63).

• Metastatic disease at diagnosis and visceral metastases independently increased progression risk (HR: 1.45 and 1.25, respectively).

• Oral chemotherapy (primarily capecitabine, less often vinorelbine) emerged as a potentially preferable option for selected patients. Among those with visceral metastases, compared with intravenous treatment, oral chemotherapy was associated with better survival outcomes (HR: 1.52, P = 0.04).

• Intravenous chemotherapy and endocrine therapy were associated with shorter progression-free survival than oral chemotherapy (HR: 1.45 and 1.38, respectively), but no significant overall survival difference was found.

Study Methods

The median age at diagnosis was 52.4 years.

• 67.6% of patients received endocrine therapy combined with CDK4/6 inhibitors as first-line treatment.

• The remaining 32.4% received this treatment in the second line.

• After progression, 221 patients continued endocrine treatment (everolimus + exemestane or endocrine therapy alone), while 285 received chemotherapy (intravenous or oral).

The study's primary endpoint, defined as the time from starting the first systemic treatment to progression or death from any cause, was progression-free survival (PFS) . The secondary endpoint , defined as the time from progression during endocrine therapy + CDK4/6 inhibition to death from any cause, was overall survival (OS) .

Conclusion and Commentary

This study identified CDK4/6 treatment duration as a key determinant in metastatic breast cancer management and associated visceral metastases with poorer outcomes. It particularly emphasized that oral chemotherapy may offer selected patients similar survival to intravenous chemotherapy, with fewer adverse effects and greater convenience .

Study Limitations

Its retrospective design allows selection bias and uncontrolled confounding. Patients rechallenged with CDK4/6 inhibitors were excluded. Insufficient tumor genomic data prevented assessment of genetic factors affecting treatment response.