526 Background: The PALLAS trial (NCT02513394) investigated the efficacy of the addition of palbociclib (palbo) to standard adjuvant endocrine therapy (ET) to reduce breast cancer recurrence. Previous analyses of this trial have not shown significant benefit of combination palbo+ET over ET alone. Given prior data showing that extent of neutropenia is associated with response to palbo and other cell cycle-specific therapies, we evaluated whether extent of neutropenia could identify responders to palbo in the adjuvant setting. Methods: PALLAS is a global, open-label, phase III trial that randomized patients (pts) with stage II-III hormone-receptor positive, HER2-negative breast cancer to receive ET for ≥5 years with or without standard-dose palbo for 2 years in 28-day cycles. The primary endpoint is invasive disease-free survival (iDFS). For this exploratory analysis, the palbo population was classified into pts with treatment-emergent high-grade neutropenia (HGN) with maximum grade ≥3 (absolute neutrophil count <1000), or low-grade/no neutropenia (LGN) with maximum grade <2; these groups were compared to each other and to the ET alone group for 5-year iDFS outcomes. Logistic regression examined individual baseline characteristics associated with HGN during the first 3 cycles within the palbo group. Impact of HGN during the first 3, 6, and 12 cycles on iDFS was tested using univariate and multivariable landmark Cox regression. Results: The safety population included 5736 pts, 2840 allocated to palbo+ET, 2896 to ET alone. Prior publications reported no new safety signals, low rates of serious infection, and no grade 5 treatment-related events. The palbo+ET group consisted of 1006 (35.4%) LGN and 1834 (64.6%) HGN. 5-year iDFS results are shown in the table. Pts who received palbo+ET and developed HGN by the end of cycle 6 had significantly improved 5-year iDFS compared to those who received ET alone (p=0.04), which remained statistically significant when adjusting for body mass index (BMI), prior chemotherapy, and race. Multivariable logistic regression showed lower BMI, prior chemotherapy, Asian race, and prior mastectomy were significantly associated with HGN (all p<0.05). Conclusions: In this exploratory analysis of the phase III PALLAS adjuvant trial, addition of palbo to ET appeared to be superior to ET alone in pts who developed HGN in the first 6 cycles of treatment but not in those who had LGN. These findings are consistent with observations in the metastatic setting suggesting that neutropenia could be a useful biomarker for palbo concentration and efficacy. Clinical trial information: NCT02513394 . Maximum grade neutropenia measured at end of cycle: 5-year iDFS Palbo+ET HGN (%) Palbo+ET LGN (%) ET alone (%) Hazard Ratio p-value 3 84.9 84.4 1.06 0.54 84.9 82.9 1.17 0.06 6 85.6 84.9 1.08 0.44 85.6 83.4 1.19 0.04 12 86.3 85.9 1.06 0.57 86.3 85.0 1.12 0.20

IMPORTANCE Triple-negative breast cancer is an aggressive subtype with a high incidence in young patients, a high incidence in non-Hispanic Black women, and a high risk of progression to metastatic cancer, a devastating sequela with a 12- to 18-month life expectancy. Until recently, one strategy for treating early-stage triple-negative breast cancer was chemotherapy after surgery. However, it was not known whether the addition of immune therapy to postsurgery chemotherapy would be beneficial. OBJECTIVE To evaluate the addition of immune therapy in the form of atezolizumab to postoperative chemotherapy in patients with the high-risk triple-negative breast cancer subtype. DESIGN, SETTING, AND PARTICIPANTS In this open-label international randomized phase 3 trial conducted in more than 330 centers in 31 countries, patients undergoing surgery as initial treatment for stage II or III triple-negative breast cancer were enrolled between August 2, 2018, and November 11, 2022. The last patient follow-up was on August 18, 2023. INTERVENTIONS Patients were randomized (1:1) to receive standard chemotherapy for 20 weeks with (n = 1101) or without (n =1098) the immune therapy drug atezolizumab for up to 1 year. MAIN OUTCOMES AND MEASURES The primary end point was invasive disease-free survival (time between randomization and invasive breast cancer in the same or opposite breast, recurrence elsewhere in the body, or death from any cause). RESULTS The median age of enrolled patients was 53 years and most self-reported as being of Asian or White race and neither Latino nor Hispanic ethnicity. The study independent data monitoring committee halted enrollment at 2199 of 2300 planned patients. All patients stopped atezolizumab followinga planned early interim and futility analysis. The trial continued to a premature final analysis. With invasive disease-free survival events in 141 patients (12.8%) treated with atezolizumab-chemotherapy and 125 (11.4%) with chemotherapy alone (median follow-up, 32 months), the final stratified invasive disease-free survival hazard ratio was 1.11(95% CI, 0.87-1.42; P = .38). Compared with chemotherapy alone, the regimen of atezolizumab plus chemotherapy was associated with more treatment-related grade 3 or 4 adverse events (54% vs 44%) but similar incidences of fatal adverse events (0.8% vs 0.6%) and adverse events leading to chemotherapy discontinuation. Chemotherapy exposure was similar in the 2 treatment groups. CONCLUSIONS AND RELEVANCE The addition of the immune therapy drug atezolizumab to chemotherapy after surgery did not provide benefit among patients with triple-negative breast cancer who are at high risk of recurrent disease.

Background It is unclear whether some patients with high-risk breast cancer do not warrant adjuvant dose-dense chemotherapy due to small expected absolute benefit. Methods The phase 3 PANTHER trial (NCT00798070) compared adjuvant sequential epirubicin/cyclophosphamide (EC) and docetaxel (D) administered in either tailored dose-dense (tDD EC/D) or standard interval schedule (FEC/D) to patients with high-risk resected early breast cancer (n = 2003). We compared outcomes across key subgroups of interest, evaluated the performance of the online prognostication and treatment benefit estimation tool PREDICT and conducted a subpopulation treatment effect pattern plot (STEPP) analysis. Primary endpoint was breast cancer recurrence free survival (BCRFS). Findings Median follow-up was 10.3 years. Treatment with tDD EC/D improved 10-year BCRFS across all subgroups including according to menopausal status, with an absolute benefit of 2% or more, as well as in luminal (Hazard Ratio [HR] = 0.83, 95% Confidence Interval [CI] 0.65-1.05) and Human Epidermal Growth Factor Receptor 2 (HER2) positive (HR = 0.53, 95% CI 0.30-0.93), but not triple negative breast cancer patients (HR = 1.02, 95% CI 0.66-1.57). PREDICT underestimated overall survival in the entire population and across all subgroups. In STEPP analysis, absolute benefit from tDD EC/D in BCRFS was stable across risk-defined subpopulations, from 3.8% in the lowest risk patients to 3.6% in the highest risk ones. There was no differential treatment effect over time. Interpretation We could not reliably identify any subgroup not benefiting from dose-dense treatment, which should be considered for patients with primary resected high-risk breast cancer. Funding Cancerfonden, Br & ouml;stcancerf & ouml;rbundet, Radiumhemmets Forskningsfonder, Amgen, Roche, sanofi-aventis. Copyright (c) 2024 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background: The Clinical Treatment Score post-5 years (CTS5) is a clinicopathological tool designed to estimate late distant recurrence (LDR) in hormone receptor-positive (HR+) breast cancer patients after 5 years of adjuvant endocrine therapy (ET). While intended as a prognostic algorithm, its predictive value for ET extension remains uncertain. Methods: The score was calculated in 4931 patients from four prospective randomized ABCSG trials (ABCSG-6, -6a, -8, and -16) with 250 LDR events. We assessed its prognostic power, calibration accuracy, and predictive value. Time to LDR was analyzed using Cox regression models. Results: In our cohorts, the CTS5 provided prognostic information whether used as a continuous or categorical score. In the ABCSG-8 cohort (n = 2054) and the combined ABCSG-6+8 cohort (n = 3308), a higher continuous score was significantly associated with increased LDR risk. The categorical CTS5 showed that high-risk patients had significantly higher LDR rates compared to low- or intermediate-risk patients. The score slightly overestimated LDR risk, regardless of predicted risk. Although no significant predictive value was found on the relative scale, an absolute LDR risk reduction of 23.4 % was found in patients with a high CTS5 of 5 when extended ET was administered additional five than two years. In patients with a CTS5 of 2, no benefit was found when ET was extended to 10 instead of 7 years. Conclusion: The CTS5 is a valid tool for LDR risk stratification in HR + breast cancer, but should be used cautiously for determining benefits from ET extension, as no significant predictive value was found.

Abstract Background. The phase 3 PALLAS trial (NCT02513394) compared two years of the CDK4/6 inhibitor palbociclib with endocrine therapy of provider choice, versus endocrine therapy alone, as adjuvant treatment for patients with Stage II-III hormone receptor-positive HER2-negative (HR+/HER2-) breast cancer. Genomic subtype (PAM50 intrinsic subtype) measured from whole-transcriptome RNA sequencing data was defined in the protocol of the PALLAS trial as the primary biomarker for analysis of prediction and prognosis. Clinical data have been previously presented (Gnant et al, JCO 2022), and the trial now has 5-year median follow-up. Methods. As part of trial eligibility, all participants in PALLAS provided a tumor tissue block prior to randomization (surgical if primary resection, core biopsy if neoadjuvant treatment) for translational analyses (TRANS-PALLAS). The biorepository and laboratory were blinded to identity and processed samples in random order, to minimize bias. Nucleic acids were extracted from samples with sufficient tumor tissue and cellularity (>25 mm2 with ≥20% cancer nuclei). The Genome Sequencing Center at Washington University St. Louis performed whole-transcriptome RNA sequencing. Libraries were prepared from 1 µg DNase-1 treated total RNA, if total RNA DV200 >28 (Agilent Bioanalyzer), using an unbiased library protocol of RNA HyperPrep kit with RiboErase (HMR) (Kapa Biosystems, Wilmington, MA). 100 bp paired-end sequencing was performed on NovaSeq 6000 using S4 Reagent Kit (Illumina, San Diego, CA), with 48 libraries pooled per lane. Intrinsic subtype was determined using Bioclassifier package (Research PAM50 script, Parker et al.) only for the analysis population of primary breast cancer samples that had not been exposed to prior neoadjuvant therapy. Invasive disease-free survival (IDFS) will be visualized using Kaplan-Meier plots, with log-rank test between groups. Cox models of proportional hazards will be developed to evaluate prognosis adjusted for known clinical covariates, or for predictive interactions. The pre-defined level of significance is a two-sided 0.05. Results. From the total study population of 5796 enrolled patients, 4655 tissue blocks had sufficient tumor content to process for RNA, with 3931 yielding sufficient RNA for sequencing, and 2669/4655 (57.3%) submitted tissue blocks had DV200 ≥28 and were successfully sequenced. Clinical unblinding revealed 2370 unique patients (1182 in the palbociclib treatment arm and 1188 in the control arm) with intrinsic subtype defined from their untreated primary tumor: 1555 (65.6%) luminal A, 287 (12.1%) luminal B, 167 (7.0%) HER2-enriched, 310 (13.1%) basal-like, 51 (2.2%) normal-like. We will report the results for association of molecular subtype, proliferation score, and Risk of Recurrence (ROR) scores with invasive disease-free survival (IDFS) by treatment arm at the meeting. Conclusions. The TRANS-PALLAS cohort represents one of the largest biorepositories of HR+/HER2- early breast cancer reflecting contemporary systemic management in the framework of a prospectively randomized global trial. Required tumor block submission in this phase 3 trial yielded data from unbiased whole-transcriptome RNA sequencing of the primary tumor prior to treatment from 41% of the PALLAS participants. The proportion of luminal A cancers was unexpectedly high (66%), indicating a lower-risk distribution of cancers in this population. The planned analyses of prediction and prognosis are ongoing and those results will be presented at the time of the meeting. Support: AFT, ABCSG, Pfizer, ECOG-ACRIN, NSABP Foundation, GBG, BIG; Clinicaltrials.gov Identifier: NCT02513394; https://acknowledgments.alliancefound.org Citation Format: Daniel Stover, Dominik Hlauschek, Erica Mayer, W. Fraser Symmans, Mark Watson, Iros Barozzi, Martin Filipits, Karla Ballman, Meritxell Bellet- Ezquerra, Justin Balko, Gabor Rubovszky, Nicholas Zdenkowski, Adam Brufsky, Guenther Steger, Claudine Isaacs, Sibylle Loibl, Fernando Henao, Meredith Regan, Yuan Liu, Christian Fesl, Patrick O'Brien, Angela DeMichele, Michael Gnant, Otto Metzger. Protocol-defined biomarker analysis in the PALLAS (AFT-05) adjuvant trial: Genomic subtype derived from RNA sequencing of HR+/HER2- early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS03-07.

Abstract Background: Early stage triple negative breast cancer (TNBC) is associated with a high risk of distant relapse. ALEXANDRA/IMpassion030 is a global, prospective, randomized, open-label, phase 3 trial that investigated the efficacy, safety and pharmacokinetic profile of adjuvant atezolizumab plus standard anthracycline/taxane chemotherapy (arm A) versus chemotherapy alone (arm B) in early-stage TNBC. Methods: ALEXANDRA/IMpassion030 (NCT03498716) aimed to randomize (1:1) 2300 patients with operable stage II-III TNBC, confirmed by central pathology review. Patients were stratified by type of surgery (breast conserving versus mastectomy), nodal status (0 versus 1-3 versus &gt;=4 nodes), and centrally assessed PD-L1 status (IC 0 vs &gt;=1% ). Adjuvant chemotherapy consisted of weekly paclitaxel 80 mg/m2 for 12 weeks followed by dose dense anthracycline (epirubicin 90 mg/m2 or doxorubicin 60 mg/m2) and cyclophosphamide 600 mg/m2 for 4 doses every 2 weeks given concomitantly with atezolizumab 840 mg every 2 weeks followed by maintenance atezolizumab 1200 mg every 3 weeks until completion of 1 year of atezolizumab (Arm A) or the same chemotherapy regimen (T-EC/AC) alone (Arm B). The primary endpoint was invasive disease-free survival (iDFS); secondary endpoints included, iDFS in the PD-L1 positive and lymph node-positive subpopulations, overall survival, safety, patient functioning and health related quality of life (HRQoL). On the 14th of November 2022, following an IDMC recommendation, the study accrual was temporarily stopped. In February 2023, the protocol was amended in order for the IDMC to perform an early interim analysis of efficacy and futility, at approximately 62% of the planned (390) iDFS events. The futility boundary was set to a Hazard Ratio (HR) &gt; 1. Results: The IDMC recommendations of 15th March 2023 reported that the primary endpoint crossed the futility boundary, accrual to the study was permanently stopped and the experimental treatment was discontinued. Between August 2018 and November 2022, the study enrolled 2199 patients, with 1101 randomised to the atezolizumab arm (A) and 1098 to the control arm (B). At a median follow-up of 25.3 months, 239 (10.9%) iDFS events were observed in the 2199 enrolled patients; 127 versus 112 iDFS events were observed (61.3% of 390) in the A versus B arms respectively, HR 1.12, (95% confidence interval, CI, 0.87, 1.45). In the PD-L1 positive subgroup, (1567/2199 patients, 71.3%), 77 versus 73 iDFS events were observed in the A versus B arms respectively, HR 1.03, (95% CI 0.75, 1.42). Among patients with lymph node positive tumors (1066/2199 patients, 48.5%), 86 versus 66 iDFS events were observed in the A versus B arm respectively, HR 1.41, (95% CI 1.02, 1.96). Incidence of adverse events grade &gt;=3 was 58.01% versus 48.15% in the A versus B arms, including death in 1.01% (11) and 0.55% (6) of patients, respectively. Conclusions: Crossing the pre-specified futility boundary of HR &gt; 1 provides evidence that adjuvant atezolizumab is very unlikely to improve invasive disease-free survival when added to adjuvant anthracycline and taxane based chemotherapy in patients with stage II-III triple-negative breast cancer. With longer treatment exposure in the atezolizumab arm (A), adverse events were more frequent but consistent with the atezolizumab safety profile. No new or unexpected safety issue was identified. Citation Format: Michail Ignatiadis, Andrew Bailey, Heather McArthur, Sarra El-Abed, Evandro de Azambuja, Otto Metzger, Steve Chui, Max Dieterich, Thomas Perretti, Guenther Steger, Jacek Jassem, Soo Chin Lee, Michaela Higgins, José Zarbá, Marcus Schmidt, Henry Gomez, Angel Guerrero-Zotano, Luca Moscetti, Joanne Win Yang Chiu, Carter DuFrane, Vanessa Honvault, Rosa Altarcheh, Luciana Molinero, Andrew Ellingson, Elisabetta Munzone, Noa Efrat Ben-Baruch, Emilio Bajetta, Shinji Ohno, Seock-Ah Im, Gustavo Werutsky, Einav Gal-Yam, Xavier Gonzalez-Farré, Ling-Ming Tseng, William Jacot, Oleg Gluz, Zhimin Shao, Yaroslav Shparyk, Ivan Sinielnikov, Zimina Anastasia, Aleksandr Vasiliev, Esther Shearer-Kang, Eric Winer, Diogo Martins-Branco, Shona Fielding, David Cameron, Giuseppe Viale, Shigehira Saji, Richard Gelber, Martine Piccart. Adding atezolizumab to adjuvant chemotherapy for stage II and III triple-negative breast cancer is unlikely to improve efficacy: interim analysis of the ALEXANDRA/IMpassion030 phase 3 trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS01-03.

The Clinical Treatment Score post-5 years (CTS5) is an easy-to-use tool estimating the late distant recurrence (LDR) risk in patients with hormone receptor-positive breast cancer after 5 years of endocrine therapy (ET). Apart from evaluating the prognostic value and calibration accuracy of CTS5, the aim of this study is to clarify if this score is able to identify patients at higher risk for LDR who will benefit from extended ET. Prognostic power, calibration, and predictive value of the CTS5 was tested in patients of the prospective ABCSG-06 and -0a6 trials (n = 1254 and 860 patients, respectively). Time to LDR was analyzed with Cox regression models. Higher rates of LDR in the years five to ten were observed in high- and intermediate-risk patients compared to low-risk patients (HR 4.02, 95

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Although dose-dense adjuvant chemotherapy administered once every 2 weeks leads to superior outcomes compared with standard regimens once every 3 weeks, the observed improvement is largely limited to studies using the suboptimal paclitaxel schedule once every 3 weeks as control. PANTHER is an international phase III trial which compared sequential epirubicin/cyclophosphamide and docetaxel administered either once every 2 or once every 3 weeks, with tailored dosing at the dose-dense schedule according to hematologic toxicity. In this end-of-study analysis, the median follow-up was 10.3 years. Compared with standard adjuvant chemotherapy, dose-dense treatment improved breast cancer recurrence-free survival (hazard ratio [HR], 0.80 [95% CI, 0.65 to 0.98]; P = .030), event-free survival (HR, 0.78 [95% CI, 0.65 to 0.94]; P = .009), and distant disease-free survival (HR, 0.79 [95% CI, 0.64 to 0.98]; P = .030) while the improvement in overall survival was not statistically significant (HR, 0.82 [95% CI, 0.65 to 1.04]; P = .109). To our knowledge, this is the first trial that confirms the benefit of a dose-dense regimen over a control regimen containing docetaxel once every 3 weeks.

Background: The widespread adoption of adjuvant bisphosphonate therapy for postmenopausal early breast cancer (EBC) patients was based on results of the Early Breast Cancer Trialist Group (EBCTCG) meta-analysis. Despite multiple regimens evaluated, there was no signal of varying efficacy with type, dose/dose intensity of bisphosphonate administra-tion. We evaluated the effect of early treatment cessation using long-term outcome data from the ABCSG-12 trial.Patients and methods: ABCSG-12 randomized 1803 hormone-receptor positive EBC patients on ovarian suppression between 1999 and 2006 to receive 4 mg zoledronic acid 6-monthly or not (and tamoxifen or anastrozole, 2:2 factorial design). In the current study, we evaluated whether the number of zoledronate infusions had an impact on breast cancer-specific out-comes. We hypothesized that amongst patients who received at least one zoledronate infusion, the number of infusions had no effect on outcomes. Time-to-event endpoints were analysed with Cox models and Kaplan Meier curves starting from a 3-year landmark. BMD analysis was restricted to patients who participated in the BMD sub-study.Results: 725 patients who received at least one zoledronate infusion were included in the time -to-event analysis. There was no statistically significant difference in disease-free or overall sur-vival in the patients who received <6 zoledronate infusions (n = 170) compared to those who received >7 zoledronate infusions (n = 555). Conclusions: Comparable to efforts to de-escalate treatment duration in metastatic bone dis-ease, there was no evidence to indicate that a reduced number of zoledronate infusions is asso-ciated with reduced adjuvant efficacy. Further studies to define optimal regimens of adjuvant bone-targeted therapies are required. Crown Copyright 2022 Published by Elsevier Ltd. All rights reserved.

<p>Supplementary table legend</p>

<p>Patients characteristics of the overall population</p>

Abstract Background: The results of the Early Breast Cancer Trialist Group (EBCTCG) meta-analysis (Lancet 2015) led to the widespread adoption of bisphosphonates as adjuvant therapy for postmenopausal early-stage breast cancer (EBC). Despite evaluating multiple bisphosphonate agents and regimens, there was no signal of varying efficacy with different agents, routes of administration or dose/dose intensity. We evaluated the question of treatment de-escalation using long-term outcome data from the prospective randomized ABCSG-12 trial. Patients and methods: Between 1999 and 2006, ABCSG-12 accrued 1803 patients with hormone-receptor positive EBC on ovarian function suppression for three years that were randomized to receive 4 mg zoledronic acid 6-monthly or not (and tamoxifen or anastrozole, in a 2:2 factorial design). In the current retrospective study, we evaluated whether the number of zoledronate infusions actually received had an impact on breast cancer-specific and fragility fracture outcomes. Based on the results of the EBCTCG meta-analysis, we hypothesized that amongst patients who receive less infusions than the planned seven zoledronate infusion in this trial, the number of infusions has no differential effect on these outcomes. Time to event endpoints were analyzed with Cox models and Kaplan Meier curves starting from a 3-year landmark. BMD subset analyses were restricted to patients who participated in the BMD sub-study with available BMD data. Results: 725 patients who received at least one zoledronate infusion were included in the time-to-event-analysis. There was no statistically significant difference in disease-free survival (adjusted HR 0.83, 95% CI 0.48–1.44, p=0.51) or overall survival (HR 0.97, 95% 0.30-3.11, p=0.96) in patients who received ≤6 zoledronate infusions (n=170) compared to those who received ≥7 zoledronate infusions (n=555) (adjusted HR 0.83, 95% CI 0.48 – 1.44, p=0.51). Both subgroups show stable lumbar spine and total hip BMD measurements across the five years. Conclusions: Comparable to the metastatic bone disease and fragility fracture settings, there was no evidence observed to indicate that a reduced number of zoledronate infusions is associated with reduced adjuvant efficacy. Further studies to define optimal regimens of adjuvant bone-targeted therapies (prospective evaluation of “how-low-can-you-go”) are required. Table 1: Multivariate Cox Regression: DFS and OS Table 2: BMD and percent change from baseline at the total hip and lumbar spine (L1-L4) over 60 months Citation Format: Ana-Alicia Beltran-Bless, Mark Clemons, Christian Fesl, Dominik Hlauschek, Lidija Soelkner, Gregory R. Pond, Lisa Vandermeer, Richard Greil, Marija Balic, Vesna Bjelic-Radisic, Christian F. Singer, Guenther Steger, Ruth Helfgott, Daniel Egle, Simon P. Gampenrieder, Stephanie Kacerovsky-Strobl, Christoph Suppan, Magdalena Ritter, Gabriel Rinnerthaler, Georg Pfeiler, Hannes Fohler, John Hilton, Michael Gnant. De-escalation of bone-targeted treatment: Does the number of 6-monthly adjuvant zoledronate infusions received affect treatment efficacy for early breast cancer? A sub-study of ABCSG-12 [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-04.

<p>Supplemental Table 1. ypT0+ypN0 vs. HER2 ratios Supplemental Table 2. ypT0is+ypN0 vs. HER2 ratios Supplemental Table 3. ypT0is vs. HER2 ratios</p>

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.

Data on the accuracy of intraoperative resection margin assessment and its influence on survival after neoadjuvant therapy (NT) are scarce. In the present study, we analyzed the accuracy of resection margin assessment by intraoperative frozen section (IFS) in the prospectively randomized neoadjuvant clinical trials ABCSG 24 and ABCSG 34.164 patients with early breast cancer who received NT within the ABCSG 24 and ABCSG 34 trials between 2005 and 2015, and received IFS resection margin assessment were included in our analysis. Resection margin status by IFS was compared to subsequent FFPE resection margin status, which was considered the gold standard. According to the rate of FFPE-based false-negative and false-positive diagnoses, we determined sensitivity and specificity of IFS. Correlation of IFS diagnosis with definitive FFPE assessment was described by Cohen´s kappa coefficient, the distributional probability was analyzed by McNemar test. The association of patient- and tumor-related factors (menopausal status, residual tumor size, tumor grade, lymph node status, multifocality, DCIS component, lymph vessel invasion, ER/PR/HER2/Ki67 expression and RCB category) with correct IFS diagnosis was analyzed by chi2 test and Fisher´s exact test. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using Kaplan-Meier method and log-rank test. Median age of patients was 55 years. IFS diagnosis for negative margins (no tumor on ink) was correct in 131 (80%) cases, translating into a sensitivity of 0.571 and specificity of 0.877 (false negative rate: 43%, false positive rate 12%). Correlation coefficient for IFS and FFPE diagnosis yielded a Cohen´s kappa value of 0.459. 58 patients (35%) were re-excised during the first operation, in 27 patients (17%), a second surgical intervention was performed. Overall re-excision rates in patients with true positive, false positive and false negative IFS diagnoses were 96%, 93% and 78%, respectively. Rate of second surgical interventions in patients with true positive, false positive and false negative IFS diagnoses were 38%, 7% and 44%, respectively. Correct IFS diagnosis correlated with smaller residual tumor size (p=0.032), lymph node status (p=0.007), HER2 negativity (p=0.049), presence of a DCIS component (p=0.013) and absence of lymph vessel invasion (p=0.007). Despite of re-operation resulting in negative margins, false negative IFS diagnosis was associated with worse recurrence-free survival (p=0.0278). The impact of IFS diagnosis on OS did not reach statistical significance (p=0.0995), although patients with false negative IFS diagnosis showed a shorter OS. IFS assessment of margins after NT displayed high specificity and limited sensitivity in the ABCSG 24 and ABCSG 34 trials. Residual tumor size, lymph node status, HER2 positivity, presence of a DCIS component and lymph vessel invasion correlated with accuracy of IFS. Patients with false negative IFS margin status showed a significantly shorter RFS despite of a second intervention yielding negative margins. Larger studies are needed to confirm the effects of IFS margin assessment on OS. Our data could help to lower rates of subsequent surgical interventions for re-excision after NT and identify patients by the above mentioned tumor characteristics who are at an increased risk of recurrence despite negative margin status. Citation Format: Karin Rokitte, Kristina Tendl-Schulz, Ulrike Heber, Kerstin Wimmer, Rupert Bartsch, Stephanie Kacerovsky-Strobl, Georg Pfeiler, Günther G. Steger, Christian F. Singer, Dominik Hlauschek, Michael Gnant, Florian Fitzal, Zsuzsanna Bago-Horvath. Accuracy and predictive value of resection margin assessment by intraoperative frozen section after neoadjuvant therapy: An analysis of the ABCSG 24 and 34 trials [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-02-07.