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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.

Purpose: Sentinel lymph node resection (SNR) may reduce morbidity while providing the same clinical utility as conventional axillary dissection (AD). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 is a randomized phase III trial comparing SNR immediately followed by AD (SNAD) to SNR and subsequent AD if SN is positive. We report the definitive patient-reported outcomes (PRO) comparisons., Patients and Methods: Eligible patients had clinically node-negative, operable invasive breast cancer. The PRO substudy included all SN-negative participants enrolled May 2001 to February 2004 at community institutions in the United States (n = 749; 78% age > or = 50; 87% clinical tumor size < or = 2.0 cm; 84% lumpectomy; 87% white). They completed questionnaires presurgery, 1 and 2 to 3 weeks postoperatively, and every 6 months through year 3. Arm symptoms, arm use avoidance, activity limitations, and quality of life (QOL) were compared with intent-to-treat two-sample t-tests and repeated measures analyses., Results: Arm symptoms were significantly more bothersome for SNAD compared with SNR patients at 6 months (mean, 4.8 v 3.0; P < .001) and at 12 months (3.6 v 2.5; P = .006). Longitudinally, SNAD patients were more likely to experience ipsilateral arm and breast symptoms, restricted work and social activity, and impaired QOL (P < or = .002 all items). From 12 to 36 months, fewer than 15% of either SNAD or SNR patients reported moderate or greater severity of any given symptom or activity limitation., Conclusion: Arm morbidity was greater with SNAD than with SNR. Despite considerable fears about complications from AD for breast cancer, this study demonstrates that initial problems with either surgery resolve over time.

Purpose: This report describes interventions undertaken by the National Surgical Adjuvant Breast and Bowel Project (NSABP) to improve compliance with patient-reported outcome (PRO) assessments in the setting of multicenter cancer clinical trials. We describe the effectiveness of several interventions and of observational factors., Methods: PRO submission rates were analyzed for the following three NSABP protocols: the Study of Raloxifene and Tamoxifen (STAR), B-32, and B-35. Institutions participating in protocol B-35 were randomly assigned to receive automated reminders of upcoming assessments or not. Compliance was analyzed with a logistic repeated measures mixed modeling., Results: Compliance was high in the three protocols, with rates greater than 80% for nearly all time points. Institutions were a significant source of variability (P < .01). The largest institutions had the highest compliance in STAR (odds ratio [OR] = 0.68 for < 50 participants enrolled and OR = 0.82 for 50 to 99 participants enrolled v larger institutions; P < .001). Midsized institutions had highest compliance in B-32 (OR = 4.63 for 31 to 50 patients enrolled and OR = 3.12 for > 50 patients enrolled v small institutions; P = .007). Compliance increased with participant age in STAR (OR = 0.57, 0.89, and 1.01 for ages < 50, 50 to 60, and 60 to 70 years, respectively, v > 70 years; P < .001). Race was significant in B-32 (OR = 2.63 for white v nonwhite; P < .001) and in STAR (OR = 1.41 for white v nonwhite; P < .001). Treatment group was significant in B-32 (OR = 0.74; P = .006). The B-35 prospective reminder did not improve compliance significantly (P = .30), but in B-32, delinquency sanctions were significant (OR = 1.56; P = .007)., Conclusion: Compliance in NSABP PRO studies is higher now than a decade ago. Results for compliance initiatives were mixed. Age and race are important factors, but institutional variation remains significant and largely unexplained.