Browsing by Subject "Hormonal antineoplastic agents"

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Adjuvant Palbociclib for Early Breast Cancer: The PALLAS Trial Results (ABCSG-42/AFT-05/BIG-14-03)
    (American Society of Clinical Oncology, 2022) Gnant, Michael; Dueck, Amylou C.; Frantal, Sophie; Martin, Miguel; Burstein, Hal J.; Greil, Richard; Fox, Peter; Wolff, Antonio C.; Chan, Arlene; Winer, Eric P.; Pfeiler, Georg; Miller, Kathy D.; Colleoni, Marco; Suga, Jennifer M.; Rubovsky, Gabor; Bliss, Judith M.; Mayer, Ingrid A.; Singer, Christian F.; Nowecki, Zbigniew; Hahn, Olwen; Thomson, Jacqui; Wolmark, Norman; Amillano, Kepa; Rugo, Hope S.; Steger, Guenther G.; Hernando Fernández de Aránguiz, Blanca; Haddad, Tufia C.; Perelló, Antonia; Bellet, Meritxell; Fohler, Hannes; Metzger Filho, Otto; Jallitsch-Halper, Anita; Solomon, Kadine; Schurmans, Céline; Theall, Kathy P.; Lu, Dongrui R.; Tenner, Kathleen; Fesl, Christian; DeMichele, Angela; Mayer, Erica L.; PALLAS groups and investigators; Medicine, School of Medicine
    Purpose: Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor-positive breast cancer has not been confirmed. Patients and methods: In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer-free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. Results: Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. Conclusion: At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor-positive breast cancer.
  • Thumbnail Image
    Item
    A SNP in Steroid Receptor Coactivator-1 Disrupts a GSK3β Phosphorylation Site and Is Associated with Altered Tamoxifen Response in Bone
    (Oxford University Press, 2012-02) Hartmaier, R.J.; Richter, A.S.; Gillihan, R.M.; Sallit, J.Z.; McGuire, S.E.; Wang, J.; Lee, A.V.; Osborne, C.K.; O'Malley, B.W.; Brown, P.H.; Xu, J.; Skaar, Todd C.; Philips, S.; Rae, J.M.; Azzouz, F.; Li, L.; Hayden, J.; Henry, N.L.; Nguyen, A.T.; Stearns, V.; Hayes, D.F.; Flockhart, D.A.; Oesterreich, S.
    The coregulator steroid receptor coactivator (SRC)-1 increases transcriptional activity of the estrogen receptor (ER) in a number of tissues including bone. Mice deficient in SRC-1 are osteopenic and display skeletal resistance to estrogen treatment. SRC-1 is also known to modulate effects of selective ER modulators like tamoxifen. We hypothesized that single nucleotide polymorphisms (SNP) in SRC-1 may impact estrogen and/or tamoxifen action. Because the only nonsynonymous SNP in SRC-1 (rs1804645; P1272S) is located in an activation domain, it was examined for effects on estrogen and tamoxifen action. SRC-1 P1272S showed a decreased ability to coactivate ER compared with wild-type SRC-1 in multiple cell lines. Paradoxically, SRC-1 P1272S had an increased protein half-life. The Pro to Ser change disrupts a putative glycogen synthase 3 (GSK3)β phosphorylation site that was confirmed by in vitro kinase assays. Finally, knockdown of GSK3β increased SRC-1 protein levels, mimicking the loss of phosphorylation at P1272S. These findings are similar to the GSK3β-mediated phospho-ubiquitin clock previously described for the related coregulator SRC-3. To assess the potential clinical significance of this SNP, we examined whether there was an association between SRC-1 P1272S and selective ER modulators response in bone. SRC-1 P1272S was associated with a decrease in hip and lumbar bone mineral density in women receiving tamoxifen treatment, supporting our in vitro findings for decreased ER coactivation. In summary, we have identified a functional genetic variant of SRC-1 with decreased activity, resulting, at least in part, from the loss of a GSK3β phosphorylation site, which was also associated with decreased bone mineral density in tamoxifen-treated women.
  • Thumbnail Image
    Item
    Treatment Exposure and Discontinuation in the PALbociclib CoLlaborative Adjuvant Study of Palbociclib With Adjuvant Endocrine Therapy for Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Early Breast Cancer (PALLAS/AFT-05/ABCSG-42/BIG-14-03)
    (American Society of Clinical Oncology, 2022) Mayer, Erica L.; Fesl, Christian; Hlauschek, Dominik; Garcia-Estevez, Laura; Burstein, Harold J.; Zdenkowski, Nicholas; Wette, Viktor; Miller, Kathy D.; Balic, Marija; Mayer, Ingrid A.; Cameron, David; Winer, Eric P.; Ponce Lorenzo, José Juan; Lake, Diana; Pristauz-Telsnigg, Gunda; Haddad, Tufia C.; Shepherd, Lois; Iwata, Hiroji; Goetz, Matthew; Cardoso, Fatima; Traina, Tiffany A.; Sabanathan, Dhanusha; Breitenstein, Urs; Ackerl, Kerstin; Metzger Filho, Otto; Zehetner, Karin; Solomon, Kadine; El-Abed, Sarra; Puyana Theall, Kathy; Lu, Dongrui Ray; Dueck, Amylou; Gnant, Michael; DeMichele, Angela; Medicine, School of Medicine
    Purpose: The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. Methods: Patients with stage II-III HR+, HER2- disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. Results: Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non-protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). Conclusion: Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.