Biomarkers Lend a Hand Determining ER-Positive Breast Cancer Treatment

Physicians face the significant challenge of determining which patients with estrogen receptor-positive (ER+) breast cancer will respond to standard therapy and who will eventually discontinue therapy due to adverse events. Predicting how patients will respond to first-line therapy may be made easier with the help of 2 biomarkers, according to a study published by Nature Communications.

The authors of the study believe that retinoblastoma protein (Rb) and cytoplasmic cyclin E biomarkers could determine which patients are best suited to receive conventional therapy.

The authors also discovered that combining current treatments with an autophagy inhibitor requires only one-fifth of the dosage of standard treatment, according to the study. This discovery could significantly reduce side effects and improve quality of life.

“Our findings could impact the majority of ER+ and HER2-negative breast cancers accounting for about 60% of advanced breast cancers,” said lead researcher Khandan Keyomarsi, PhD.

Standard treatment with palbociclib—a CDK4/6 inhibitor—has adverse side effects and not all patients with ER+ breast cancer respond to it. Frequently, cancer cells evade attack by activating autophagy, which allows the cells to survive without nutrients.

Combining palbociclib with an autophagy inhibitor in cells that express normal Rb and nuclear cyclin E was observed to reduce the dose of palbociclib needed, according to the study.

The authors report that the drugs work together to induce cell deterioration in Rb-positive cytoplasmic cyclin E-negative cancer, according to the study.

“We demonstrated for the first time evidence that Rb and cytoplasmic cyclin E status have a very strong effect on predicting response to the current standard first-line therapy for this population of patients, hormonal therapy plus palbociclib,” Dr Keyomarsi said. “We also discovered that by inhibiting the pathway, such as autophagy that causes tumor cells to escape palbociclib growth inhibition, CDK4/6 inhibitor was more effective.”

Deregulation of cell checkpoint proteins results in unchecked cellular growth, which is characteristic of cancer.

Certain CDK4/6 inhibitors have shown potential to treat numerous solid tumors. Palbociclib has previously demonstrated efficacy in clinical trials of ER+ breast cancers, doubling progression-free survival compared with other drugs, according to the study. The drug is currently being evaluated in other cancers.

“Data provided through The Cancer Genome Atlas revealed alterations in the CDK4/6/cyclin D pathway in about 35% of the patients, making them an ideal population for targeting CDK4/6,” Dr Keyomarsi said. “Our study revealed that inhibition of CDK4/6 and autophagy pathways cooperate to induce sustained growth inhibition and senescence in vitro and in vivo, in breast and other solid tumors and showed how autophagy inhibition can significantly decrease the dose of palbociclib required to treat breast cancer patients. We believe this new strategy can improve the efficacy of other CDK4/6 inhibitor treatments like ribociclib and abemaciclib.”

The authors discovered that Rb and cyclin E status can accurately predict response to a combination of CDk4/6 and autophagy inhibitors in preclinical models. They also found that inhibiting autophagy reversed palbociclib resistance, according to the study.

The investigators plan to conduct additional clinical studies based on these findings, with the aim of developing novel treatments.

“Palbociclib resistance is a significant limitation of this treatment which is not curative and does not prolong survival even though transient responses and prolongation of response have formed the basis of FDA approval,” Dr Keyomarsi concluded. “Our study provides evidence that models of hormone receptor-negative cancer and even non-breast cancer malignancies can respond to the combination of palbociclib and autophagy inhibition, when selected based on Rb and cyclin E isoform status, representing a completely new therapeutic opportunity for these cancers.”