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Palbociclib may have antiproliferative effects when used as a neoadjuvant therapy for women with early stage breast cancer.
Monica Arnedos, MD
Palbociclib, which is approved for the treatment of advanced breast cancer, may have antiproliferative effects in early breast tumors, according to a study that examined biomarker changes of patients with different subtypes of early-stage tumors from the 2016 AACR Annual Meeting.
In the randomized phase II PreOperative Palbociclib (POP) trial, single-agent palbociclib administered preoperatively significantly decreased Ki67 levels, a cellular marker for proliferation.
“Single-agent palbociclib is effective in decreasing Ki67 in early breast cancer, and the impact of its efficacy is higher in hormone receptor (HR)-positive/HER2-negative as compared to HER2-positive or triple-negative breast cancer,” said Monica Arnedos, MD, an assistant professor at Gustave Roussy Cancer Campus in Villejuif, France. “The magnitude of this activity was higher than expected.”
Palbociclib is an inhibitor of CDK 4 and 6. It is approved for use in combination with letrozole in the frontline setting and with fulvestrant as a second-line therapy for postmenopausal women with estrogen receptor-positive, HER2-negative metastatic breast cancer. In the PALOMA-1 and -3 trials, palbociclib plus an aromatase inhibitor doubled the median progression-free survival rates versus endocrine therapy alone.
There are no data yet about the drug’s potential efficacy in early breast cancer, and no biomarkers of efficacy have been determined. In this randomized clinical trial, Arnedos and colleagues examined the expression of various biomarkers in 100 patients with different subtypes of early breast cancer. In the study, single-agent palbociclib 125 mg orally was administered for 14 days before breast cancer surgery to 74 patients with early breast cancer. The 26 patients in the control arm received no treatment.
The study was initially open to patients with HR-positive, HER2-negative tumors irrespective of menopausal status. The design was amended to allow patients with HR-negative and/or HER2-positive tumors. In the final population, 84% of patients had tumors that were HR-positive/HER2-negative.
Tissue samples were taken at baseline and at surgery. The primary endpoint was percentage of patients with a log-transformed Ki67 (InKi67) < 1 at Day 15. Secondary endpoints were changes from baseline in Ki67, safety, and, in exploratory analyses, the association between pretreatment tumor characteristics and proliferative changes.An antiproliferative response in the tumor, as measured by InKi67 levels <1, was observed in 58% of the patients who received palbociclib, compared with 12% of controls (P <.001), Arnedos reported.
The change was most significant in patients with HR-positive/HER2-negative breast cancer. In this subset, 70% of palbociclib-treated patients achieved this reduction in proliferation, compared with 9% of controls. The endpoint was not achieved with the drug among patients with HER2-positive or triple-negative cancer.
“The effect of palbociclib on cell proliferation is different between HR-positive/HER2-negative and the other subtypes, with an interaction test of P =.002,” she noted.
Change in Ki67 from baseline was also highly significant for the HR-positive/HER2-negative subgroup (P <.0001), but was not significant for the HER2-positive or triple-negative groups (P =.331).
“Ki67 is not a validated surrogate of drug efficacy for HER2-positive and triple-negative breast cancer,” she said, adding that the study lacked enough patients with HR-negative breast cancer to interpret findings for that group.
Other analyses demonstrated that palbociclib significantly decreased phospho-Rb (retinoblastoma protein, which activates the cell cycle on), compared with controls. Additionally, a subset of patients with HR-positive/HER2-negative cancers showed no decrease in phosphor-Rb and this correlated with lack of Ki67 response; these patients may have primary resistance to the drug.
The only molecular alteration associated with decreased Ki67 by palbociclib was phosphor-Rb at surgery. Rb, p16, pER, pAKT expression, as well as CCND1 amplification and presence of PIK3CA mutation at baseline were not predictive of a decrease in proliferation by palbociclib. Additionally, CDK1 and CD25C expression were weak predictors of InKi67 at surgery.
“Genes whose expression was most significantly affected by palbociclib short-duration treatment were related to proliferation and the cell cycle,” she explained.
Session moderator Nancy Davidson, MD, director of the University of Pittsburgh Cancer Institute, emphasized that Ki67 is a well-established pharmacodynamic marker for response to endocrine neoadjuvant treatment, but its clinical utility has been limited by poor inter-observer reproducibility. Sixteen laboratories are now working to standardize Ki67 scoring, which should help overcome these limitations, she said.
Davidson said the small sample size and trial design preclude the ability to correlate the results with intrinsic subtypes and with clinical response. The primary objective of the study, however, was achieved, showing reductions in proliferation that were “best appreciated” in the HR-positive/HER2-negative subset.
The POP trial does, however, have implications, especially for future research, she added. Most importantly, she said, the findings suggest there may be biomarkers for response and possibly for resistance that could become clinically useful if further validated.
Arnedos M, Cheaib B, Michiels BS, et al. Anti-proliferative response and predictive biomarkers to palbociclib in early breast cancer. The Preoperative Palbociclib (POP) randomized trial. Presented at: AACR Annual Meeting 2016, New Orleans; April 16-20, 2016. Abstract CT041