Browsing by Author "Mayer, Ingrid A."
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Item Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer(Massachusetts Medical Society, 2018-07) Sparano, Joseph A.; Gray, Robert J.; Makower, Della F.; Pritchard, Kathleen I.; Albain, Kathy S.; Hayes, Daniel F.; Geyer, Charles E., Jr.; Dees, Elizabeth C.; Goetz, Matthew P.; Olson, John A., Jr.; Lively, Tracy; Badve, Sunil S.; Saphner, Thomas J.; Wagner, Lynne I.; Whelan, Timothy J.; Ellis, Matthew J.; Paik, Soonmyung; Wood, William C.; Ravdin, Peter M.; Keane, Maccon M.; Gomez Moreno, Henry L.; Reddy, Pavan S.; Goggins, Timothy F.; Mayer, Ingrid A.; Brufsky, Adam M.; Toppmeyer, Deborah L.; Kaklamani, Virginia G.; Berenberg, Jeffery L.; Abrams, Jeffrey; Sledge, George W., Jr.; Pathology and Laboratory Medicine, School of MedicineBACKGROUND The recurrence score based on the 21-gene breast cancer assay predicts chemotherapy benefit if it is high and a low risk of recurrence in the absence of chemotherapy if it is low; however, there is uncertainty about the benefit of chemotherapy for most patients, who have a midrange score. METHODS We performed a prospective trial involving 10,273 women with hormone-receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative, axillary node–negative breast cancer. Of the 9719 eligible patients with follow-up information, 6711 (69%) had a midrange recurrence score of 11 to 25 and were randomly assigned to receive either chemoendocrine therapy or endocrine therapy alone. The trial was designed to show noninferiority of endocrine therapy alone for invasive disease–free survival (defined as freedom from invasive disease recurrence, second primary cancer, or death). RESULTS Endocrine therapy was noninferior to chemoendocrine therapy in the analysis of invasive disease–free survival (hazard ratio for invasive disease recurrence, second primary cancer, or death [endocrine vs. chemoendocrine therapy], 1.08; 95% confidence interval, 0.94 to 1.24; P=0.26). At 9 years, the two treatment groups had similar rates of invasive disease–free survival (83.3% in the endocrine-therapy group and 84.3% in the chemoendocrine-therapy group), freedom from disease recurrence at a distant site (94.5% and 95.0%) or at a distant or local–regional site (92.2% and 92.9%), and overall survival (93.9% and 93.8%). The chemotherapy benefit for invasive disease–free survival varied with the combination of recurrence score and age (P=0.004), with some benefit of chemotherapy found in women 50 years of age or younger with a recurrence score of 16 to 25. CONCLUSIONS Adjuvant endocrine therapy and chemoendocrine therapy had similar efficacy in women with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who had a midrange 21-gene recurrence score, although some benefit of chemotherapy was found in some women 50 years of age or younger.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 MedicinePurpose: 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.Item Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer(Massachusetts Medical Society, 2019-06-20) Sparano, Joseph A.; Gray, Robert J.; Ravdin, Peter M.; Makower, Della F.; Pritchard, Kathleen I.; Albain, Kathy S.; Hayes, Daniel F.; Geyer, Charles E.; Dees, Elizabeth C.; Goetz, Matthew P.; Olson, John A.; Lively, Tracy; Badve, Sunil S.; Saphner, Thomas J.; Wagner, Lynne I.; Whelan, Timothy J.; Ellis, Matthew J.; Paik, Soonmyung; Wood, William C.; Keane, Maccon M.; Gomez Moreno, Henry L.; Reddy, Pavan S.; Goggins, Timothy F.; Mayer, Ingrid A.; Brufsky, Adam M.; Toppmeyer, Deborah L.; Kaklamani, Virginia G.; Berenberg, Jeffrey L.; Abrams, Jeffrey; Sledge, George W.; Pathology and Laboratory Medicine, School of MedicineBACKGROUND The use of adjuvant chemotherapy in patients with breast cancer may be guided by clinicopathological factors and a score based on a 21-gene assay to determine the risk of recurrence. Whether the level of clinical risk of breast cancer recurrence adds prognostic information to the recurrence score is not known. METHODS We performed a prospective trial involving 9427 women with hormone-receptor–positive, human epidermal growth factor receptor 2–negative, axillary node–negative breast cancer, in whom an assay of 21 genes had been performed, and we classified the clinical risk of recurrence of breast cancer as low or high on the basis of the tumor size and histologic grade. The effect of clinical risk was evaluated by calculating hazard ratios for distant recurrence with the use of Cox proportional-hazards models. The initial endocrine therapy was tamoxifen alone in the majority of the premenopausal women who were 50 years of age or younger. RESULTS The level of clinical risk was prognostic of distant recurrence in women with an intermediate 21-gene recurrence score of 11 to 25 (on a scale of 0 to 100, with higher scores indicating a worse prognosis or a greater potential benefit from chemotherapy) who were randomly assigned to endocrine therapy (hazard ratio for the comparison of high vs. low clinical risk, 2.73; 95% confidence interval [CI], 1.93 to 3.87) or to chemotherapy plus endocrine (chemoendocrine) therapy (hazard ratio, 2.41; 95% CI, 1.66 to 3.48) and in women with a high recurrence score (a score of 26 to 100), all of whom were assigned to chemoendocrine therapy (hazard ratio, 3.17; 95% CI, 1.94 to 5.19). Among women who were 50 years of age or younger who had received endocrine therapy alone, the estimated (±SE) rate of distant recurrence at 9 years was less than 5% (≤1.8±0.9%) with a low recurrence score (a score of 0 to 10), irrespective of clinical risk, and 4.7±1.0% with an intermediate recurrence score and low clinical risk. In this age group, the estimated distant recurrence at 9 years exceeded 10% among women with a high clinical risk and an intermediate recurrence score who received endocrine therapy alone (12.3±2.4%) and among those with a high recurrence score who received chemoendocrine therapy (15.2±3.3%). CONCLUSIONS Clinical-risk stratification provided prognostic information that, when added to the 21-gene recurrence score, could be used to identify premenopausal women who could benefit from more effective therapy.Item Double-Blind Phase III Trial of Adjuvant Chemotherapy With and Without Bevacizumab in Patients With Lymph Node-Positive and High-Risk Lymph Node-Negative Breast Cancer (E5103)(American Society of Clinical Oncology, 2018-09) Miller, Kathy D.; O’Neill, Anne; Gradishar, William; Hobday, Timothy J.; Goldstein, Lori J.; Mayer, Ingrid A.; Bloom, Stuart; Brufsky, Adam M.; Tevaarwerk, Amye J.; Sparano, Joseph A.; Le-Lindqwister, Nguyet Anh; Hendricks, Carolyn B.; Northfelt, Donald W.; Dang, Chau T.; Sledge, George W.; Medicine, School of MedicinePurpose Bevacizumab improves progression-free survival but not overall survival in patients with metastatic breast cancer. E5103 tested the effect of bevacizumab in the adjuvant setting in patients with human epidermal growth factor receptor 2-negative disease. Patients and Methods Patients were assigned 1:2:2 to receive placebo with doxorubicin and cyclophosphamide (AC) followed by weekly paclitaxel (arm A), bevacizumab only during AC and paclitaxel (arm B), or bevacizumab during AC and paclitaxel followed by bevacizumab monotherapy for 10 cycles (arm C). Random assignment was stratified and bevacizumab dose adjusted for choice of AC schedule. Radiation and hormonal therapy were administered concurrently with bevacizumab in arm C. The primary end point was invasive disease-free survival (IDFS). Results Four thousand nine hundred ninety-four patients were enrolled. Median age was 52 years; 64% of patients were estrogen receptor positive, 27% were lymph node negative, and 78% received dose-dense AC. Chemotherapy-associated adverse events including myelosuppression and neuropathy were similar across all arms. Grade ≥ 3 hypertension was more common in bevacizumab-treated patients, but thrombosis, proteinuria, and hemorrhage were not. The cumulative incidence of clinical congestive heart failure at 15 months was 1.0%, 1.9%, and 3.0% in arms A, B, and C, respectively. Bevacizumab exposure was less than anticipated, with approximately 24% of patients in arm B and approximately 55% of patients in arm C discontinuing bevacizumab before completing planned therapy. Five-year IDFS was 77% (95% CI, 71% to 81%) in arm A, 76% (95% CI, 72% to 80%) in arm B, and 80% (95% CI, 77% to 83%) in arm C. Conclusion Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2-negative breast cancer. Longer duration bevacizumab therapy is unlikely to be feasible given the high rate of early discontinuation.Item Human and Machine Intelligence Together Drive Drug Repurposing in Rare Diseases(Frontiers Media, 2021-07-28) Challa, Anup P.; Zaleski, Nicole M.; Jerome, Rebecca N.; Lavieri, Robert R.; Shirey-Rice, Jana K.; Barnado, April; Lindsell, Christopher J.; Aronoff, David M.; Crofford, Leslie J.; Harris, Raymond C.; Ikizler, T. Alp; Mayer, Ingrid A.; Holroyd, Kenneth J.; Pulley, Jill M.; Medicine, School of MedicineRepurposing is an increasingly attractive method within the field of drug development for its efficiency at identifying new therapeutic opportunities among approved drugs at greatly reduced cost and time of more traditional methods. Repurposing has generated significant interest in the realm of rare disease treatment as an innovative strategy for finding ways to manage these complex conditions. The selection of which agents should be tested in which conditions is currently informed by both human and machine discovery, yet the appropriate balance between these approaches, including the role of artificial intelligence (AI), remains a significant topic of discussion in drug discovery for rare diseases and other conditions. Our drug repurposing team at Vanderbilt University Medical Center synergizes machine learning techniques like phenome-wide association study-a powerful regression method for generating hypotheses about new indications for an approved drug-with the knowledge and creativity of scientific, legal, and clinical domain experts. While our computational approaches generate drug repurposing hits with a high probability of success in a clinical trial, human knowledge remains essential for the hypothesis creation, interpretation, "go-no go" decisions with which machines continue to struggle. Here, we reflect on our experience synergizing AI and human knowledge toward realizable patient outcomes, providing case studies from our portfolio that inform how we balance human knowledge and machine intelligence for drug repurposing in rare disease.Item Prospective Validation of a 21-Gene Expression Assay in Breast Cancer(Massachusetts Medical Society, 2015-11) Sparano, Joseph A.; Gray, Robert J.; Makower, Della F.; Pritchard, Kathleen I.; Albain, Kathy S.; Hayes, Daniel F.; Geyer, Charles E., Jr.; Dees, Elizabeth C.; Perez, Edith A.; Olson, John A., Jr.; Zujewski, JoAnne; Lively, Tracy; Badve, Sunil S.; Saphner, Thomas J.; Wagner, Lynne I.; Whelan, Timothy J.; Ellis, Matthew J.; Paik, Soonmyung; Wood, William C.; Ravdin, Peter; Keane, Maccon M.; Gomez Moreno, Henry L.; Reddy, Pavan S.; Goggins, Timothy F.; Mayer, Ingrid A.; Brufsky, Adam M.; Toppmeyer, Deborah L.; Kaklamani, Virginia G.; Atkins, James N.; Berenberg, Jeffrey L.; Sledge, George W.; Pathology and Laboratory Medicine, School of MedicineBACKGROUND Prior studies with the use of a prospective–retrospective design including archival tumor samples have shown that gene-expression assays provide clinically useful prognostic information. However, a prospectively conducted study in a uniformly treated population provides the highest level of evidence supporting the clinical validity and usefulness of a biomarker. METHODS We performed a prospective trial involving women with hormone-receptor–positive, human epidermal growth factor receptor type 2 (HER2)–negative, axillary node–negative breast cancer with tumors of 1.1 to 5.0 cm in the greatest dimension (or 0.6 to 1.0 cm in the greatest dimension and intermediate or high tumor grade) who met established guidelines for the consideration of adjuvant chemotherapy on the basis of clinicopathologic features. A reverse-transcriptase–polymerase-chain-reaction assay of 21 genes was performed on the paraffin-embedded tumor tissue, and the results were used to calculate a score indicating the risk of breast-cancer recurrence; patients were assigned to receive endocrine therapy without chemotherapy if they had a recurrence score of 0 to 10, indicating a very low risk of recurrence (on a scale of 0 to 100, with higher scores indicating a greater risk of recurrence). RESULTS Of the 10,253 eligible women enrolled, 1626 women (15.9%) who had a recurrence score of 0 to 10 were assigned to receive endocrine therapy alone without chemotherapy. At 5 years, in this patient population, the rate of invasive disease–free survival was 93.8% (95% confidence interval [CI], 92.4 to 94.9), the rate of freedom from recurrence of breast cancer at a distant site was 99.3% (95% CI, 98.7 to 99.6), the rate of freedom from recurrence of breast cancer at a distant or local–regional site was 98.7% (95% CI, 97.9 to 99.2), and the rate of overall survival was 98.0% (95% CI, 97.1 to 98.6). CONCLUSIONS Among patients with hormone-receptor–positive, HER2-negative, axillary node–negative breast cancer who met established guidelines for the recommendation of adjuvant chemotherapy on the basis of clinicopathologic features, those with tumors that had a favorable gene-expression profile had very low rates of recurrence at 5 years with endocrine therapy alone.Item Race, Ethnicity, and Clinical Outcomes in Hormone Receptor-Positive, HER2-Negative, Node-Negative Breast Cancer in the Randomized TAILORx Trial(Oxford University Press, 2021-04-06) Albain, Kathy S.; Gray, Robert J.; Makower, Della F.; Faghih, Amir; Hayes, Daniel F.; Geyer, Charles E., Jr.; Dees, Elizabeth C.; Goetz, Matthew P.; Olson, John A., Jr.; Lively, Tracy; Badve, Sunil S.; Saphner, Thomas J.; Wagner, Lynne I.; Whelan, Timothy J.; Ellis, Matthew J.; Wood, William C.; Keane, Maccon M.; Gomez, Henry L.; Reddy, Pavan S.; Goggins, Timothy F.; Mayer, Ingrid A.; Brufsky, Adam M.; Toppmeyer, Deborah L.; Kaklamani, Virginia G.; Berenberg, Jeffrey L.; Abrams, Jeffrey; Sledge, George W., Jr.; Sparano, Joseph A.; Pathology and Laboratory Medicine, School of MedicineBackground: Black race is associated with worse outcomes in early breast cancer. We evaluated clinicopathologic characteristics, the 21-gene recurrence score (RS), treatment delivered, and clinical outcomes by race and ethnicity among women who participated in the Trial Assigning Individualized Options for Treatment. Methods: The association between clinical outcomes and race (White, Black, Asian, other or unknown) and ethnicity (Hispanic vs non-Hispanic) was examined using proportional hazards models. All P values are 2-sided. Results: Of 9719 eligible women with hormone receptor-positive, HER2-negative, node-negative breast cancer, there were 8189 (84.3%) Whites, 693 (7.1%) Blacks, 405 (4.2%) Asians, and 432 (4.4%) with other or unknown race. Regarding ethnicity, 889 (9.1%) were Hispanic. There were no substantial differences in RS or ESR1, PGR, or HER2 RNA expression by race or ethnicity. After adjustment for other covariates, compared with White race, Black race was associated with higher distant recurrence rates (hazard ratio [HR] = 1.60, 95% confidence intervals [CI] = 1.07 to 2.41) and worse overall survival in the RS 11-25 cohort (HR = 1.51, 95% CI = 1.06 to 2.15) and entire population (HR = 1.41, 95% CI = 1.05 to 1.90). Hispanic ethnicity and Asian race were associated with better outcomes. There was no evidence of chemotherapy benefit for any racial or ethnic group in those with a RS of 11-25. Conclusions: Black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy in the Trial Assigning Individualized Options for Treatment. Similar to Whites, Black women did not benefit from adjuvant chemotherapy if the 21-gene RS was 11-25. Further research is required to elucidate the basis for this racial disparity in prognosis.Item 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 MedicinePurpose: 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.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 MedicinePurpose: 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.