Immediate zoledronate in postmenopausal women receiving letrozole preserved BMD and is associated with improved DFS compared with letrozole alone. Clinical Trials Registration No NCT00171340.
PURPOSE CDK4/6 inhibitors are used to treat estrogen receptor (ER)–positive metastatic breast cancer (BC) in combination with endocrine therapy. PALLET is a phase II randomized trial that evaluated the effects of combination palbociclib plus letrozole as neoadjuvant therapy. PATIENTS AND METHODS Postmenopausal women with ER-positive primary BC and tumors greater than or equal to 2.0 cm were randomly assigned 3:2:2:2 to letrozole (2.5 mg/d) for 14 weeks (A); letrozole for 2 weeks, then palbociclib plus letrozole to 14 weeks (B); palbociclib for 2 weeks, then palbociclib plus letrozole to 14 weeks (C); or palbociclib plus letrozole for 14 weeks. Palbociclib 125 mg/d was administered orally on a 21-days-on, 7-days-off schedule. Core-cut biopsies were taken at baseline and 2 and 14 weeks. Coprimary end points for letrozole versus palbociclib plus letrozole groups (A v B + C + D) were change in Ki-67 (protein encoded by the MKI67 gene; immunohistochemistry) between baseline and 14 weeks and clinical response (ordinal and ultrasound) after 14 weeks. Complete cell-cycle arrest was defined as Ki-67 less than or equal to 2.7%. Apoptosis was characterized by cleaved poly (ADP-ribose) polymerase. RESULTS Three hundred seven patients were recruited. Clinical response was not significantly different between palbociclib plus letrozole and letrozole groups ( P = .20; complete response + partial response, 54.3% v 49.5%), and progressive disease was 3.2% versus 5.4%, respectively. Median log-fold change in Ki-67 was greater with palbociclib plus letrozole compared with letrozole (−4.1 v −2.2; P < .001) in the 190 evaluable patients (61.9%), corresponding to a geometric mean change of −97.4% versus −88.5%. More patients on palbociclib plus letrozole achieved complete cell-cycle arrest (90% v 59%; P < .001). Median log-fold change (suppression) of cleaved poly (ADP-ribose) polymerase was greater with palbociclib plus letrozole versus letrozole (−0.80 v −0.42; P < .001). More patients had grade 3 or greater toxicity on palbociclib plus letrozole (49.8% v 17.0%; P < .001) mainly because of asymptomatic neutropenia. CONCLUSION Adding palbociclib to letrozole significantly enhanced the suppression of malignant cell proliferation (Ki-67) in primary ER-positive BC, but did not increase the clinical response rate over 14 weeks, which was possibly related to a concurrent reduction in apoptosis.
Background: Letrozole (LET) is an accepted adjuvant endocrine therapy for hormone receptor-positive (HR+) postmenopausal early breast cancer (EBC) with superior efficacy to tamoxifen. Long term aromatase inhibitors (AI) treatment reduces estrogen levels well below postmenopausal levels leading to acceleration of bone loss. Zoledronic acid (ZOL), effectively inhibits osteoclastic bone resorption in both benign and malignant bone disorders. The primary analysis at 12 months of the Z-FAST, ZO-FAST and E-ZO-FAST studies demonstrated that lumbar spine (LS) bone mineral density (BMD) loss secondary to LET can effectively be prevented by ZOL. In addition, the 36 month (mo) follow-up for ZO-FAST demonstrated ZOL improved disease free survival (DFS). This 5 yr analysis of ZO-FAST reports the final BMD results, long term safety and DFS. Additionally, we examine the characteristics of patients in the delayed arm who required ZOL to maintain BMD. Materials and Methods: 1065 postmenopausal women (PMW) hormone receptor positive (HR+) EBC receiving LET (2.5 mg qd x 5 yrs) with a BMD T-score ≥-2 were randomized to immediate ZOL arm (IMZOL, n=532) vs delayed ZOL arm (DZOL, n=533). ZOL was initiated in DZOL when postbaseline T-score decreased to <-2 SD, a non-traumatic or asymptomatic fracture occurred. Patients were followed for disease recurrence (DR) and survival until 5 years after the closure of enrollment. Results: At 60 mo, LS BMD is maintained with IMZOL with a mean percent change from baseline of 4.3 vs -5.4 in DZOL (least square difference of 10%, P<0.0001). 144 pts (26.9%) in the DZOL started ZOL at a median of 12.8 mo (range 0.9-62.1 mo). Patients on the DZOL who started ZOL were 81/165 (49%) initially osteopenic (-2≤ Tscore <-1.0) and 63/370 (17%) had a normal BMD (Tscore >-1.0). Additional risk factors regarding bone health were evaluated in a subset of patients. The fracture rate for the two arms is 39 (7.4%) in IMZOL and 38 (7.1%) DZOL. A total of 104 patients (31 DR and 11 deaths in the IMZOL vs. 48 DR and 14 deaths in the DZOL) experienced a DFS event. The hazard ratio for the comparison is 0.66 with a 95% confidence interval (0.44, 0.97), (p = 0.034). In the IMZOL, there were 29 patients (5.5%) with a distant recurrence vs 41 (7.7%) in the DZOL. Patients with local recurrences were 5 (0.9%) vs 12 (2.3%) in the respective arms. Over the 5 year study duration, osteonecrosis of the jaw (ONJ) was found in 4/669 patients who received ZOL (0.6%). Adverse events remain as previously reported and are consistent with the known safety profile of both study drugs. Conclusion: The 5 yr final analysis confirms the primary endpoint that ZOL 4mg IV q 6 mos is effective in preventing bone loss associated with adjuvant AI therapy in HR+ PMW with EBC. With longer follow up, the data continues to demonstrate a significant DFS benefit in the upfront ZOL arm supporting the antitumor efficacy of ZOL seen in several tumor types. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P5-11-01.
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