SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. Breast cancer is the second leading cause of cancer death in women, in the U.S.
About 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors, and HR-positive/HER2-negative breast cancer is the most frequently diagnosed molecular subtype. About 90% of all breast cancers are detected at an early stage, and these patients are often cured with a combination of surgery, radiotherapy, chemotherapy, and hormone therapy. However approximately 20% of patients will experience local recurrence or distant relapse during the first 10 years of treatment. This may be more relevant for those with high risk disease, among whom the risk of recurrence is even greater during the first 2 years while on adjuvant endocrine therapy, due to primary endocrine resistance. More than 75% of the early recurrences are seen at distant sites. Factors associated with high risk of recurrence in HR-positive, HER2-negative early breast cancer include positive nodal status, the number of positive nodes, large tumor size (5 cm or more), and high tumor grade (Grade 3).
Cyclin Dependent Kinases (CDKs) play a very important role to facilitate orderly and controlled progression of the cell cycle. Genetic alterations in these kinases and their regulatory proteins have been implicated in various malignancies. CDK 4 and 6 phosphorylate RetinoBlastoma protein (RB), and initiate transition from the G1 phase to the S phase of the cell cycle. RetinoBlastoma protein has antiproliferative and tumor-suppressor activity. Phosphorylation of RB protein nullifies its beneficial activities. CDK4 and CDK6 are activated in HR-positive breast cancer, by binding to D-cyclins in the ER-positive breast cancer cell, promoting breast cancer cell proliferation. Further, there is evidence to suggest that endocrine resistant breast cancer cell lines depend on CDK4 for cell proliferation. The understanding of the role of CDKs in the cell cycle, has paved the way for the development of CDK inhibitors.
It has been shown that CDK4/6 inhibitors in combination with endocrine therapy improves Progression Free Survival (PFS) as well as Overall Survival (OS) when given as initial treatment (first-line) and after prior endocrine monotherapy (second-line), in patients with HR-positive, HER2-negative advanced breast cancer. Treatment guidelines recommend first-line use of CDK4/6 inhibitors along with endocrine therapy, but evidence of superiority of first-line use over second-line based on a head-to-head comparison is lacking.
SONIA is a real-world, randomized, investigator-initiated, nationwide, Phase III trial, conducted to evaluate the efficacy, safety and cost-effectiveness of CDK4/6 inhibitors added to either first or second-line endocrine therapy, in patients with HR-positive, HER2-negative advanced breast cancer, who have received no prior therapy for their advanced disease. In this study, 1050 pre and postmenopausal women (N=1050) with measurable or evaluable disease, who received no prior therapy for advanced breast cancer, were randomized 1:1 to receive first-line treatment with a non-steroidal Aromatase Inhibitor and a CDK4/6 inhibitor, followed upon progression by Fulvestrant (strategy A) or first-line treatment with a non-steroidal Aromatase Inhibitor, followed upon progression by Fulvestrant and CDK4/6 inhibitor (strategy B). Both treatment groups were well balanced. Neoadjuvant/adjuvant therapy was allowed if the disease-free interval after non-steroidal Aromatase Inhibitor therapy was more than 12 months. The choice of CDK4/6 inhibitor was a stratification factor and was left to the discretion of the treating physician. The Primary endpoint was time from randomization to second objective disease progression, as assessed by local investigators, or death (PFS2). Secondary endpoints include Overall Survival (OS), Safety, Quality of Life, and cost-effectiveness.
At a median follow-up was 37.7 months, the median duration of CDK4/6 inhibitor treatment/usage was 24.6 months in the first-line group and 8.1 months in the second-line group. The median PFS with strategy A as expected was significantly longer in the CDK4/6 inhibitor group than in the non-steroidal Aromatase Inhibitor group (24.7 months and 16.1 months respectively, HR=0.59; P<0.0001). However, with regards to PFS2, there was no significant difference between the two treatment groups. The median PFS2 was 31.0 months with strategy A versus 27.8 months with strategy B (HR=0.89; P=0.14) and this similar PFS2 treatment effect was consistent across pre-defined subgroups. There was no significant difference in Overall Survival between the two treatment groups (HR=0.98; P=0.83).
There were more grade 3 or 4 adverse events when CDK4/6 inhibitors were used in the first-line setting and the use of strategy A increased the cost of treatment by an average of $200,000 per patient. Quality of life, as measured by Functional Assessment of Cancer Therapy – Breast (FACT-B) total score, was not different between the 2 arms.
It was concluded that first-line use of CDK4/6 inhibitor along with endocrine therapy does not provide statistically significant and clinically meaningful Progression Free Survival benefit compared to second-line use in women with HR-positive and HER2-negative advanced breast cancer. The authors added that second-line use may thus be a preferred option for the majority of these patients, as the use in first-line prolongs the time on CDK4/6 inhibitors by over 16 months and increases toxicity and cost of treatment. It should however be noted that in this study, patients received single-agent Fulvestrant as second-line treatment which may not be the standard treatment intervention, given the approval of Alpelisib for patients with PIK3CA mutations. Treatment selection based on biomarkers testing therefore is important. Based on the SONIA trial data, offering endocrine therapy alone in the first line setting may not be inappropriate for favorable risk patients without high visceral tumor burden.
Primary outcome analysis of the phase 3 SONIA trial (BOOG 2017-03) on selecting the optimal position of cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors for patients with hormone receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). Sonke GS, Van Ommen-Nijhof A, Wortelboer N, et al. DOI: 10.1200/JCO.2023.41.17_suppl. LBA1000 Journal of Clinical Oncology 41, no. 17_suppl (June 10, 2023) LBA1000
