Meeting News CoveragePerspective

Palbociclib exhibits antiproliferative activity in untreated early-stage breast cancer

NEW ORLEANS — Short-term preoperative therapy with palbociclib appeared to decrease Ki67 cellular proliferation in women with early-stage breast cancer, according to results of a randomized trial presented at the American Association for Cancer Research Annual Meeting.

“The use of targeted therapies has been increasing in the last few years,” Monica Arnedos, MD, assistant professor of medicine at Gustave Rousey Cancer Campus in Villejuif, France, said in a press release. “It is crucial to determine that these drugs do hold activity against cancer cells. In the case of palbociclib [Ibrance, Pfizer], no predictive biomarkers have been identified to date.”

Monica Arnedos

Monica Arnedos

Palbociclib is approved in combination with letrozole to treat postmenopausal women with ER-positive, HER-2–negative metastatic breast cancer; however, no data exist on its efficacy in the early-stage setting.

The analysis included data from 100 women who underwent surgery for early-stage breast cancer. The majority of patients (93%) had hormone receptor-positive disease and 8% had HER-2–positive breast cancer.

The researchers randomly assigned patients 3:1 to 125 mg daily oral palbociclib for 14 days until the day before surgery (n = 74), or to no presurgical treatment (n = 26). They extracted formalin-fixed paraffin-embedded and frozen samples at baseline and at time of surgery.

Immunostaining of Ki67, RB, pRB, pAKT and pER; fluorescence in situ hybridization; and gene expression arrays were performed before and after treatment, with PIK3CA and p53 mutations assessed prior to treatment.

Antiproliferative response — defined as a natural logarithm of Ki67 below 1 at day 15 — served as the primary study objective.

Women assigned palbociclib exhibited significantly decreased pRB (P = .0027), and a greater proportion of women in the palbociclib arm experienced an antiproliferative response (58% vs. 10%; P = .0003).

Women in the palbociclib arm also had a significantly higher mean decrease in Ki67 on day 15 (P < .0001).

Researchers found the change in Ki67, a marker of cell proliferation, was greatest among women with hormone receptor-positive, HER-2–negative breast cancer. Among these women, 72% in the palbociclib arm demonstrated decreased Ki67 compared with 5% of the control arm.

The researchers did not observe a Ki67 response in women with triple-negative or HER-2–positive breast cancer (P = .0038 for interaction test).

Baseline RB, pRB or p16 status did not predict palbociclib’s effect on Ki67 status. However, palbociclib’s effect in Ki67 correlated with pRB changes from baseline (Spearman rank correlation, r = 0.42; P < .0001).

Arnedos acknowledged the small number of patients with HER-2–positive breast cancer as a study limitation.

Additional genetic analyses remain ongoing.

“Palbociclib works in untreated early-stage breast cancer,” Arnedos said. “[T]he magnitude of this activity was higher than expected.” – by Cameron Kelsall

Reference:

Arnedos M, et al. Abstract CT041. Presented at: American Association for Cancer Research Annual Meeting; April 16-20, 2016; New Orleans.

Disclosure: Pfizer and the Breast Cancer Research Foundation funded this study. Arnedos reports research funding from Pfizer during the conduct of the study, as well as honoraria from Novartis.

NEW ORLEANS — Short-term preoperative therapy with palbociclib appeared to decrease Ki67 cellular proliferation in women with early-stage breast cancer, according to results of a randomized trial presented at the American Association for Cancer Research Annual Meeting.

“The use of targeted therapies has been increasing in the last few years,” Monica Arnedos, MD, assistant professor of medicine at Gustave Rousey Cancer Campus in Villejuif, France, said in a press release. “It is crucial to determine that these drugs do hold activity against cancer cells. In the case of palbociclib [Ibrance, Pfizer], no predictive biomarkers have been identified to date.”

Monica Arnedos

Monica Arnedos

Palbociclib is approved in combination with letrozole to treat postmenopausal women with ER-positive, HER-2–negative metastatic breast cancer; however, no data exist on its efficacy in the early-stage setting.

The analysis included data from 100 women who underwent surgery for early-stage breast cancer. The majority of patients (93%) had hormone receptor-positive disease and 8% had HER-2–positive breast cancer.

The researchers randomly assigned patients 3:1 to 125 mg daily oral palbociclib for 14 days until the day before surgery (n = 74), or to no presurgical treatment (n = 26). They extracted formalin-fixed paraffin-embedded and frozen samples at baseline and at time of surgery.

Immunostaining of Ki67, RB, pRB, pAKT and pER; fluorescence in situ hybridization; and gene expression arrays were performed before and after treatment, with PIK3CA and p53 mutations assessed prior to treatment.

Antiproliferative response — defined as a natural logarithm of Ki67 below 1 at day 15 — served as the primary study objective.

Women assigned palbociclib exhibited significantly decreased pRB (P = .0027), and a greater proportion of women in the palbociclib arm experienced an antiproliferative response (58% vs. 10%; P = .0003).

Women in the palbociclib arm also had a significantly higher mean decrease in Ki67 on day 15 (P < .0001).

Researchers found the change in Ki67, a marker of cell proliferation, was greatest among women with hormone receptor-positive, HER-2–negative breast cancer. Among these women, 72% in the palbociclib arm demonstrated decreased Ki67 compared with 5% of the control arm.

The researchers did not observe a Ki67 response in women with triple-negative or HER-2–positive breast cancer (P = .0038 for interaction test).

Baseline RB, pRB or p16 status did not predict palbociclib’s effect on Ki67 status. However, palbociclib’s effect in Ki67 correlated with pRB changes from baseline (Spearman rank correlation, r = 0.42; P < .0001).

Arnedos acknowledged the small number of patients with HER-2–positive breast cancer as a study limitation.

Additional genetic analyses remain ongoing.

“Palbociclib works in untreated early-stage breast cancer,” Arnedos said. “[T]he magnitude of this activity was higher than expected.” – by Cameron Kelsall

Reference:

Arnedos M, et al. Abstract CT041. Presented at: American Association for Cancer Research Annual Meeting; April 16-20, 2016; New Orleans.

Disclosure: Pfizer and the Breast Cancer Research Foundation funded this study. Arnedos reports research funding from Pfizer during the conduct of the study, as well as honoraria from Novartis.

    Perspective
    Selina Chen-Kiang

    Selina Chen-Kiang

    The antiproliferative response to palbociclib in patients with newly diagnosed early-stage breast cancer suggests the use of palbociclib as a frontline treatment. It also confirms the mechanism of palbociclib action as a CDK4/6 inhibitor, first demonstrated in the phase 1 single-agent palbociclib clinical trial in mantle cell lymphoma. This finding was subsequently confirmed in a phase 2 clinical trial that combined palbociclib with letrozole in metastatic breast cancer. Results led to FDA approval of palbociclib for treatment of breast cancer in 2015.
    The targets of palbociclib — CDK4 and CDK6 — are rarely mutated in human cancer. Therefore, it is not a surprise that palbociclib hits the intended target in all reported clinical trials as long as Rb, the substrate of CDK4 and CDK6, is expressed. Screening for Rb expression should be a requisite for palbociclib therapy. Beyond this, no other biomarkers for palbociclib have been identified. This is the most challenging and important question at hand.

    Reference:
    Leonard JP, et al. Blood. 2012;doi:10.1182/blood-2011-10-388298.
    • Selina Chen-Kiang, PhD
    • Sandra and Edward Meyer Cancer Center Weill Cornell Medicine

    Disclosures: Chen-Kiang reports no relevant financial disclosures.

    Perspective

    Window-of-opportunity studies allow for serial assessment of biomarkers in the breast and serum in the context of a brief period of drug exposure before definitive, necessary curative surgery for early-stage breast cancer. Arnedos and colleagues performed such a trial in the PreOperative Palbociclib (POP) randomized trial comparing the cyclin-dependent kinase (CDK) 4/6 cell cycle inhibitor palbociclib (Ibrance, Pfizer) in a 125-mg oral daily dose for 14 days with placebo (3:1 randomization), in a largely ER–positive and HER-2–negative population. The primary endpoint of detecting a difference in cell proliferation as measured by Ki67 at day 15 was met, leading to a press release that stated, “palbociclib works in untreated early-stage breast cancer.”

    Examining the impact of palbociclib on other indicators of antitumor activity, there was notably no increase in tumor necrosis or apoptosis and the trend, in fact, was in the direction of the placebo control arm. Given the known effects of CDK 4/6 inhibition on Rb protein, it was not surprising to see a decrease in phosphorylation of Rb (pRb) vs. placebo; pRb hypophosphorylation and decline in Ki67 were correlated, leading the authors to hypothesize that lack of Rb hypophosphorylation might represent primary resistance.

    The study does not inform us regarding what the potential impact of aromatase inhibition (AI) or estrogen receptor downregulation (SERD) — the two current clinically relevant FDA–approved uses for palbociclib in ER–positive advanced breast cancer — in combination with CDK 4/6 inhibition might be. What does adding AI or SERD to CDK 4/6 inhibitor do? So, palbociclib monotherapy “works” in early-stage breast cancer?

    In the Immediate Preoperative Anastrozole, Tamoxifen or Combined with Tamoxifen (IMPACT) trial, the 2-week Ki67 value after preoperative endocrine therapy for ER–positive breast cancer has been demonstrated to predict RFS. Does this hold true for any agent? What is the incremental advantage for the addition of palbociclib to endocrine therapy in this model — the seemingly more clinically relevant question not addressed by the POP trial? 

    Words are important. To state, based on these data, that neoadjuvant palbociclib monotherapy “works” in early breast cancer has implications. Certainly, the randomized trial data from the PALOMA suite of trials support the investigation of CDK 4/6 inhibition in earlier stage ER–positive breast cancer. The ongoing PALLAS Trial is designed to determine benefit of palbociclib on invasive DFS in early breast cancer (NCT02513394).

    The current biomarker data in POP — particularly the observation that PIK3CA mutational status was not associated with decline in Ki67, consistent with the observation that PIK3CA mutational status did not impact response to fulvestrant (Faslodex, AstraZeneca) plus palbociclib in PALOMA-3 — is useful in directing further drug and trial development. To be sure, the POP results afford a window into biology, not so much into efficacy.

    As per the experience with preoperative metformin, where Ki67 decreased and apoptosis, in fact, increased (TUNEL), “evaluation of the clinical relevance of these findings in adequately powered clinical trials using clinical trial endpoints such as survival is needed.” POP goes the weasel.

    References:

    Cristofanilli M, et al. Lancet Oncol. 2016;doi:10.1016/S1470-2045(15)00613-0.

    Dowsett M, et al. J Natl Cancer Inst. 2007;99:167-770.

    Klintman M and Dowsett M. J Natl Cancer Inst Monogr. 2015;doi:10.1093/jncimonographs/lgv002.

    Niraula D, et al. Breast Cancer Res Treat. 2012;doi:10.1007/s10549-012-2223-1.

    • Andrew D. Seidman, MD & Maura N. Dickler, MD
    • HemOnc Today Editorial Board member & Memorial Sloan Kettering Cancer Center Memorial Sloan Kettering Cancer Center

    Disclosures: Seidman reports a speakers bureau role with Novartis and consultant roles with Eli Lilly, Novartis and Pfizer. Dickler reports consultant roles with Novartis, Pfizer and Roche/Genentech and researcher support from Eli Lilly, Novartis and Roche/Genentech.

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