Browsing by Author "Mayer, Erica L."

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    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.
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    Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes
    (Springer, 2023) Lenz, Lauren; Neff, Chris; Solimeno, Cara; Cogan, Elizabeth S.; Abramson, Vandana G.; Boughey, Judy C.; Falkson, Carla; Goetz, Matthew P.; Ford, James M.; Gradishar, William J.; Jankowitz, Rachel C.; Kaklamani, Virginia G.; Marcom, P. Kelly; Richardson, Andrea L.; Storniolo, Anna Maria; Tung, Nadine M.; Vinayak, Shaveta; Hodgson, Darren R.; Lai, Zhongwu; Dearden, Simon; Hennessy, Bryan T.; Mayer, Erica L.; Mills, Gordon B.; Slavin, Thomas P.; Gutin, Alexander; Connolly, Roisin M.; Telli, Melinda L.; Stearns, Vered; Lanchbury, Jerry S.; Timms, Kirsten M.; Medicine, School of Medicine
    Purpose: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer. Methods: Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes. Results: A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2-deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy. Conclusions: This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.
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    Randomized Phase III Postoperative Trial of Platinum-Based Chemotherapy Versus Capecitabine in Patients With Residual Triple-Negative Breast Cancer Following Neoadjuvant Chemotherapy: ECOG-ACRIN EA1131
    (American Society of Clinical Oncology, 2021) Mayer, Ingrid A.; Zhao, Fengmin; Arteaga, Carlos L.; Symmans, William F.; Park, Ben H.; Burnette, Brian L.; Tevaarwerk, Amye J.; Garcia, Sofia F.; Smith, Karen L.; Makower, Della F.; Block, Margaret; Morley, Kimberly A.; Jani, Chirag R.; Mescher, Craig; Dewani, Shabana J.; Tawfik, Bernard; Flaum, Lisa E.; Mayer, Erica L.; Sikov, William M.; Rodler, Eve T.; Wagner, Lynne I.; DeMichele, Angela M.; Sparano, Joseph A.; Wolff, Antonio C.; Miller, Kathy D.; Medicine, School of Medicine
    Purpose: Patients with triple-negative breast cancer (TNBC) and residual invasive disease (RD) after completion of neoadjuvant chemotherapy (NAC) have a high-risk for recurrence, which is reduced by adjuvant capecitabine. Preclinical models support the use of platinum agents in the TNBC basal subtype. The EA1131 trial hypothesized that invasive disease-free survival (iDFS) would not be inferior but improved in patients with basal subtype TNBC treated with adjuvant platinum compared with capecitabine. Patients and methods: Patients with clinical stage II or III TNBC with ≥ 1 cm RD in the breast post-NAC were randomly assigned to receive platinum (carboplatin or cisplatin) once every 3 weeks for four cycles or capecitabine 14 out of 21 days every 3 weeks for six cycles. TNBC subtype (basal v nonbasal) was determined by PAM50 in the residual disease. A noninferiority design with superiority alternative was chosen, assuming a 4-year iDFS of 67% with capecitabine. Results: Four hundred ten of planned 775 participants were randomly assigned to platinum or capecitabine between 2015 and 2021. After median follow-up of 20 months and 120 iDFS events (61% of full information) in the 308 (78%) patients with basal subtype TNBC, the 3-year iDFS for platinum was 42% (95% CI, 30 to 53) versus 49% (95% CI, 39 to 59) for capecitabine. Grade 3 and 4 toxicities were more common with platinum agents. The Data and Safety Monitoring Committee recommended stopping the trial as it was unlikely that further follow-up would show noninferiority or superiority of platinum. Conclusion: Platinum agents do not improve outcomes in patients with basal subtype TNBC RD post-NAC and are associated with more severe toxicity when compared with capecitabine. Participants had a lower than expected 3-year iDFS regardless of study treatment, highlighting the need for better therapies in this high-risk population.
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    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.