The evolution and prognostic impact of HER2-low, HER2-ultralow, and HER2-null status in HER2-negative early breast cancer: A pre- to post-neoadjuvant chemotherapy study.

Background: The presence of Circulating Tumor Cells (CTCs) in metastatic breast cancer (BC) is associated with worse clinical outcome. Recent data showed an association between CTC(s) detection and reduced disease-free and overall survival in early disease. Patients with persisting CTC(s) after (neo)adjuvant chemotherapy might benefit from additional systemic treatment. Trastuzumab is a part of the standard of care for patients with HER2-positive BC. Recent data have reinforced the hypothesis that the therapeutic effect of trastuzumab depends on immune-related mechanisms. It has been demonstrated that trastuzumab eliminated CTC(s), irrespective of the HER2 status of the primary tumor and of CTC(s) and this was associated with improved relapse-free survival (Bozionellou et al, Clin Cancer Res 2004, Georgoulias et al Ann Oncol 2012). The Treat CTC trial is designed to explore the effect of trastuzumab in patients with HER2-negative early BC and persisting CTC(s) after (neo)adjuvant chemotherapy and surgery. Trial Design: Treat CTC trial is a multicentre (6 countries, 92 centers) European randomized phase II trial, sponsored by the EORTC and run under the BIG umbrella. It will assess the efficacy of trastuzumab in eliminating persisting CTC(s) after the completion of (neo)adjuvant chemotherapy and surgery in patients with HER2-negative early BC. Eligible patients will be randomized in a 1:1 ratio to either 6 cycles of trastuzumab or observation. Eligibility criteria: - Adequately excised HER2-negative early BC - Evidence of CTC(s) detection using the CellSearch technology after completion of (neo)adjuvant chemotherapy - Completion of adjuvant chemotherapy for node-positive disease or neoadjuvant chemotherapy with residual invasive disease in breast or lymph nodes (no complete pathological response) Specific aims: The primary objective is to evaluate whether trastuzumab decreases the detection rate of CTCs in patients with HER2-negative primary BC by comparing the trastuzumab treated arm to the observation arm. Furthermore, clinical outcomes as measured by Recurrence Free Interval (RFI), Invasive Disease Free Survival (IDFS), Disease Free Survival (DFS) and Overall Survival (OS) between the trastuzumab and observation arms will be compared. Present accrual and target accrual: It is estimated that 2175 women will be registered to include 174 patients eligible for randomization in a 1:1 ratio. Accrual is expected to be completed in 2 years. Treat CTC started patient screening in May 2013 in Belgium, in March 2014 in Germany and in June 2014 in France. An update of the proportion of patients screened versus patients randomized will be presented during SABCS. Methods: The primary test will be a one-sided test to compare the trastuzumab arm to the observation arm for the CTC(s) detection rate at week 18 (superiority test). The comparison for the primary endpoint will be performed on the intention-to-treat population using a one-sided test with overall α of 0.1. The odds ratio and its confidence interval will be estimated using a logistic regression model. The comparison of RFI, IDFS, DFS and OS will be done using a two-sided test in a proportional hazards model for cause specific hazard, adjusted for the stratification factors. Citation Format: Michail Ignatiadis, Carlo Messina, Saskia Litiere, Dimitris Mavroudis, Christian Dittrich, Anthony Kong, Wolfgang Janni, Christos Sotiriou, Martine Piccart, Jean-Yves Pierga, Brigitte Rack. Trastuzumab in HER2-negative early breast cancer as adjuvant treatment for circulating tumor cells (CTCs) (Treat CTC) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT1-2-02.

Multidisciplinary considerations in the treatment of triple-negative breast cancer.

Background This study aimed to evaluate the relationship among human epidermal growth factor receptor 2 (HER2) expression level, pathological complete response (pCR) rate of neoadjuvant chemotherapy, and prognosis in early-stage triple-negative breast cancer (TNBC). Methodology This retrospective study analyzed the relationship among HER2 expression level, pCR rate, clinicopathological factors, and prognosis in 39 patients who were diagnosed with TNBC between 2012 and 2020 at Osaka Rosai Hospital and underwent surgery after neoadjuvant chemotherapy (NAC). Results Patients' age ranged 33-86 (median = 57) years, and the observation period ranged 5-130 (median = 60) months. The HER2 expression levels were HER2 (0), HER2 (1+), and HER2 (2+, fluorescence in situ hybridization test (FISH); negative) for 18, 12, and 9 cases, respectively. The pCR rates were 38.9%, 8.3%, and 44.4% for HER2 (0), HER2 (1+), and HER2 (2+, FISH; negative), respectively, and no correlation was observed with the degree of HER2 expression. The prognosis of distant disease-free survival (DDFS) differed depending on the HER2 status (p = 0.032), and this trend was also observed in overall survival (OS) (p = 0.012). This tendency became even stronger when comparing HER2-low and HER2 (0) (p = 0.028 and p = 0.01, respectively). HER2 expression was significantly decreased from before to after NAC (p = 0.001). Conclusions HER2 expression did not correlate with the pCR rate of NAC but did correlate with DDFS and OS. Thus, patients with an HER2 (0) status are considered to have a poor prognosis and should be more aggressively considered for perioperative chemotherapy, e.g., immune checkpoint inhibitors.

Introduction: In the NATALEE-trial, Ribociclib added to adjuvant endocrine therapy significantly reduced breast cancer recurrence in the subgroup of women with high-risk, lymph node negative, hormone receptor (HR) positive, HER2 negative early stage disease. To assess the prognostic value of clinicopathological features alongside tumour stage, we compared breast cancer outcome between patients with high risk pT2N0 breast cancer (as eligible in the NATALEE-trial) and patients with a pT1-2N1 breast cancer. Methods: This is a retrospective, monocentric study with real-world data of patients with HR-positive, HER2-negative early breast cancer treated in University Hospital Leuven (UHL) between January 2000 and October 2023. We defined high risk pT2N0 disease as grade 3 tumours or grade 2 with a K67 >20% or MammaPrint (MP) clinical high risk. pT1-2N1 patients were included regardless of grade, Ki67 index or MP clinical risk score. As per intern protocol, the Ki67 index was not determined for grade 3 tumours. All patients received adjuvant radiotherapy and systemic treatment according to institutional guidelines. Our endpoints were distant disease free survival (DDFS), invasive disease free survival (IDFS) and breast cancer specific survival (BCSS). We used Kaplan–Meier analyses for the estimation of the 5,10 and 15yr DDFS and IDFS and cumulative incidence function (CIF) for BCSS, to evaluate the associations of the breast cancer’s clinicopathological features with patients’ outcomes. Analyses have been performed using SAS software. Results: We included 711 patients with pT2N0 high risk breast cancer [median age: 62yrs; (neo-)adjuvant chemotherapy 42,5%]. 538 (75.7%) were grade 3 and 173 (24.3%) grade 2 with a high Ki67 or MP clinical high risk. 1902 patients with pT1-2N1 disease were included [median age: 58yrs; (neo-)adjuvant chemotherapy 49.2%]. 533 (28.0%) were grade 3 and 1356 patients had a lower grade of which 119 (6.2%) had a Ki67 >20% while 594 (31.2%) had a Ki67 <20% and 643 (33.8%) did not have Ki67 testing. Tumours that did not have Ki67 testing were MP clinical high risk. After 15 years, DDFS were 61.5% (95% CI [56.7;65.8]) and 64.0% (95% CI [61.2;66.7]) in the pT2N0 and pT1-2N1 groups respectively (HR 1.179 [1.008;1.378], p-value 0.0392). IDFS was 57.1% (95% CI [52.4;61.5]) for the pT2N0 group and 60.6% (95% CI [57.8;63.3]) for the pT1-2N1 group (HR 1.220 [1.052;1.414], p-value 0.0085). BCSS was 85.4% (95% CI [81.8;88.6]) in the pT2N0 group and 88.3% (95% CI [86.4;90.1]) in the pT1-2N1 group. Conclusion: In this retrospective analysis DDFS, IDFS and BCSS were all numerically worse in a NATALEE eligible high risk pT2N0 population compared to a population with pT1-2N1 tumours of any grade or Ki67 index. These findings suggest that tumour biology may have a more important prognostic value than the tumour stage in HR-positive HER2 negative early stage breast cancer. Longer follow-up in the NATALEE-trial is needed to investigate the possible benefit of adding Ribociclib to adjuvant therapy based on clinicopathological features. Citation Format: Rik Van Severen, Hans Wildiers, Giuseppe Floris, Chantal Remmerie, Sileny Han, Maxime Van Houdt, Anne Deblander, Ann Smeets, Ines Nevelsteen, Caroline Weltens, Hilde Janssen, Adinda Baten, Jelle Verhoeven, Chantal Van Ongeval, Machteld Keupers, Helen De Boodt, Renate Prevos, Annelies Coessens, Valerie Celis, Kaat Van Herck, Christine Desmedt, Annouschka Laenen, Patrick Neven. Clinicopathological feature based risk of recurrence in pT2N0 HR-positive and HER2-negative early breast cancer as included in NATALEE-trial: a retrospective, real-world, monocentric study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-08-09.

CDK4/6 inhibitors as neoadjuvant treatment in breast cancer—what can we learn?

Background: Neoadjuvant chemotherapy (NAC) has been increasingly used as the frontline therapy for the management of high-risk localized breast cancer (BC). Achieving pathological complete response (pCR) following NAC is associated with significantly better disease-free (DFS) and overall survival (OS), particularly for triple negative (TN) and HER2+ breast cancer. Among HER2 negative BC, HER2-low BC is a newly defined subset that has a HER2 immunohistochemical (IHC)-1+ or 2+/ISH negative phenotype. HER2 status is divided into 3 categories: HER2 positive, HER2-low, and HER2-zero. In this study, we investigated factors for pCR in relation to HER2 status and survival after NAC. Methods: A total of 197 cases with primary BC from January 2013 to July 2023 were enrolled in this study. There were 83 HER2 positive cases (including 7 HER2 2+/ISH+ cases) and 114 HER2 (78 HER2-low and 36 HER2-0) negative cases. HER2 3+ was dichotomized according to the staining cell rate (cut-off point; 90%) into the following two groups; HER2 3+/>90% (70 cases) and HER2 3+/< 90% (6 cases). The chemotherapy regimen was anthracycline and taxane with the addition of anti-HER2 therapy if the cases were HER2-positive. The clinicopathological factors examined were age, nodal status, tumor size, ER/PgR (cut-off points; 1% and 10%), and the Ki-67 index value (cut-off points: 20% and 40%). pCR was defined as the absence of residual invasive cancer on H&E evaluation of the complete resected breast specimen (ypT0/Tis). We investigated the correlation between pCR and clinicopathological factors. The DFS and OS were calculated using the Kaplan-Meier method and analyzed using the log-rank procedure. Uni- and multivariate analyses of factors for pCR were performed using regression analysis. Results: 1. pCR was observed in 48 cases (57.8%) after NAC in the HER2 positive group and 17 cases (14.9%) in the HER2 negative group. 2. There was no significant relationship between the pCR rate and ER, PgR, Ki-67, menopausal and nodal status in the HER2 positive group. However, pCR was significantly observed more often in smaller tumors. HER2 3+( >90%) had a significantly higher pCR rate than HER2 3+(≤90%) and HER2 2+(ISH+). Multivariate analysis revealed that HER2 3+( >90%) and tumor size (≤5cm) were significant factors for pCR in HER2 positive BC cases. 3. Patients with pCR after NAC had significantly better DFS in HER2 positive BC cases. 4. There was a significant correlation between the pCR rate and ER≤10%, PgR≤10% and tumor size < 5cm in the HER2 negative BC cases. There was no relationship between the pCR rate and the HER2 status; 19.4% in HER2-0 and 12.8% in HER2-low. 5. Multivariate analysis revealed that the PgR status and tumor size were significant factors for pCR in the HER2 negative BC cases. 6. There was no significant difference in DFS between patients with pCR and non-pCR, especially in the luminal type BC cases. Moreover, no significant difference was observed between HER2-low and HER2-0. Conclusion: pCR rate after NAC was 57.8% in the HER2 positive cases and 14.9% in the HER2 negative cases. Moreover, the HER2 3+( >90%) group had a significantly higher pCR rate than the HER2 3+(≤90%) and HER2 2+(ISH+) groups. There was no correlation between the HER2 status (HER2-low and HER2-0) and pCR rate in the HER2 negative BC cases. In addition, the ER/PgR negativity (≤10%) was a significant factor for pCR in the HER2 negative cases. These findings suggest that the IHC data on the HER2 and ER/PgR status may be effective in predicting the pCR rate after NAC in BC cases. Citation Format: Nobuyuki Arima, Reiki Nishimura, Kazuhiro Muramoto, Atsushi Inayoshi, Tomio Tanigawa, Sugiko Watanabe. Studies on factors for pathological complete response after neoadjuvant chemotherapy in relation to HER2 status in primary 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 PO1-27-03.

Background: In HER2-positive (HER2+) early breast cancer (eBC) treated with neoadjuvant therapy (NAT), HER2 loss on residual disease (RD) might be correlated with a dampen survival. Recent data from the KATHERINE trial showed a maintained benefit from post-neoadjuvant trastuzumab emtansine (T-DM1) in patients with HER2 loss on RD, even if clinicopathological variables associated with HER2 loss have not been reported. We aimed to characterize the clinicopathological variables and clinical outcomes associated with HER2 loss after NAT in patients with HER2+ eBC.Methods: We retrieved data from a prospectively collected database including all consecutive HER2+ eBC patients treated with NAT at European Institute of Oncology from September 1999 to May 2018. We collected data on age, menopausal status, NAT regimen, clinical and pathological stage, as well as histological subtype and grade, hormone receptor (HR), HER2, and Ki67 status before and after NAT. HR and HER2 status were re-assessed according to the latest ASCO/CAP guidelines. Invasive disease-free survival (IDFS), distant relapse-free survival (DRFS), and overall survival (OS) were estimated using the Kaplan-Meier method and compared using the log-rank test. Univariate (UVA) and multivariate analyses (MVA) were performed to identify variables associated with survival outcomes. Variables considered in UVA included: clinical tumor stage (cT: 1-2 vs 3-4) and nodal status (cN: 0 vs 1-2-3), pre-and post-NAT HR status (neg vs pos), NAT (anti-HER2 agents: yes vs no; endocrine therapy: yes vs no), pathological tumor stage (ypT: is-0-1-2 vs 3-4) and nodal status (ypN: 0 vs 1-2-3). Variables with a p value<0.1 were included in the MVA. Results: Of 920 patients with HER2+ eBC who had received NAT, 106 (11.5%) had RD with HER2 loss and were included in the analysis. Median age was 49 yrs (range 29-76). 55 (51.9%), 48 (45.3%) and 3 (2.8%) patients were post-, pre- and peri-menopausal, respectively. Most patients had cT2 tumors (44.3%, vs cT1 3.8%, cT3 20.8%, cT4 31.1%) and cN+ disease (81% vs 19% N0). 84 patients (79.2%) were HR-pos at diagnosis. All patients received neoadjuvant chemotherapy; 73 patients (69.5%) received also anti-HER2 agents. Pathologic staging was: ypT0-is 9.4%, ypT1 47.2%, ypT2 24.5%, ypT3 17%, ypT4 1.9%; ypN0 42.5%, ypN1 27.4%, ypN2 14.2%, ypN3 16.0%. At a median follow-up of 80.8 months (interquartile range, 43.5-159.4), median IDFS, DRFS, and OS were 100 (95% CI, 61-NA), 183 (95% CI, 157-NA), and 197 months (95% CI, 130-NA), respectively. At UVA, pre-NAT HR status (p=0.088) along with cT (p=0.008) and ypN (p=0.016) status were significantly associated with IDFS. At MVA, only HR status retained significance (HR 0.48, 95% CI 0.24-0.94, p=0.032). Median IDFS in HR-pos and HR-neg patients was 109 (95% CI 68.8-NR) and 61 (95% CI 20.9-NR) months, respectively. None of the considered variables was significantly correlated with DRFS at MVA. cT (p=0.006) and ypN (p=0.003) status were also associated with OS at UVA, with ypN that remained independently associated with OS at MVA (HR 3.6, 95% CI, 1.18-11.3, p=0.025). Median OS in ypN0 vs ypN+ patients was 122 (95% CI, 84-NR) vs NR (95% CI, 213-NR), respectively. Conclusions: HER2 loss on RD can be found in ~10% of HER2+ eBCs treated with NAT. In this subset of patients, HR-negative tumors are associated with worse IDFS, warranting the investigation of escalation treatment strategies. Node-negative disease at surgery was instead associated with a significantly longer OS. Citation Format: Stefania Morganti, Antonio Marra, Giulia Viale, Paola Zagami, Elham Sajjadi, Chiara Corti, Giuseppe Curigliano, Nicola Fusco, Carmen Criscitiello. Loss of HER2 on residual disease after neoadjuvant therapy in HER2-positive early breast cancer: Clinicopathological characteristics and association with outcomes [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 P4-07-01.

Background: Bevacizumab (bev) has been used with neo-adjuvant chemotherapy (NACT) in breast cancer trials. Geparquinto reported benefit for bev in triple negative (neg) patients (pts) (pathological complete response (pCR) 36.4% vs 27.8% p=0.02), as did CALGB 40603 (pCR 52% vs 44%, p=0.057), although NSABP-B40 showed benefit in ER positive (pos) pts (pCR 23.3% vs 15.2%, p=0.008). Methods: ARTemis is a randomised phase 3 trial adding bev to NACT (docetaxel (D)-FEC). Pts with HER2-neg invasive breast cancer were eligible. Stratification was by age, ER status (neg:weak pos:strong pos), tumour size (T2:T3/4), clinical involvement of axillary nodes and inflammatory/locally advanced disease. Pts were randomised (1:1) to bev+D-FEC or D-FEC. The primary endpoint was pCR, defined as no residual invasive cancer in the breast or axillary lymph nodes after NACT. 800 pts were required to detect 10% differences in pCR rates; 85% power, 5% alpha level. Results: 800 pts were randomised from 66 UK centres (May 2009 to Jan 2013). 68% were <50 years old, 19% had inflammatory and/or locally advanced disease, 79% of tumours <50mm, 52% clinical node pos and 33% ER-neg. A 2-reader independent review of pathology reports determined whether pCR had been achieved or, at least, minimal residual disease (MRD) status. Significantly more pts on bev+D-FEC had a pCR (22% vs 17%; adjusted p=0.03) (see table). pCR rates differed significantly across ER groups (neg 38%, weak pos 39%, strong pos 7%; p<0.0001). Treatment effect of bev remained significant after adjustment for ER (p=0.03). Similarly significantly more pts on bev+D-FEC had a pCR or MRD (36% vs 29%; adjusted p=0.035). Rates differed significantly across ER groups (neg 51%, weak pos 58%, strong pos 18%; p<0.0001). Treatment effect of bev remained significant after adjustment for ER (p=0.03). D→FECBev+D→FEC % (95%CI)% (95%CI)p *$pCR in all breast tumours AND absence of disease in ax LNs in all breast tumours(n=66/393)(n=87/388) 17% (13-21%)22% (18-27%)0.03 ER neg (Allred 0-2) (n=253)32% (24-41)44% (36-54) ER weak pos (Allred 3-5) (n=67)26% (13-44)52% (34-69) ER strong pos (Allred 6-8) (n=461)7% (4-11)6% (3-10) pCR or MRD in all breast tumours(n=114/394)(n=138/388) 29% (25-34%)36% (31-41%)0.035 ER neg (Allred 0-2) (n=254)45% (36-54)56% (47-65) ER weak pos (Allred 3-5) (n=67)44% (27-62)73% (54-87) ER strong pos (Allred 6-8) (n=461)18% (13-23)19% (14-24) * Adjusted for stratification variables. $ Primary endpoint for the ARTemis trial Conclusions: ARTemis showed a significant improvement in both pCR and MRD rates with the addition of bev to D-FEC. ER-neg and ER-weak pos / HER2-neg breast cancer pts appeared to benefit most from bev, whilst pCR and MRD rates in ER-strong pos pts were lower and did not appear to benefit from bev. Our results are similar to those reported in Geparquinto and CALGB 40603. Citation Format: Helena M Earl, Louise Hiller, Janet A Dunn, Clare Blenkinsop, Louise Grybowicz, Anne-Laure Vallier, Jean Abraham, Jeremy Thomas, Elena Provenzano, Luke Hughes-Davies, Karen McAdam, Stephen Chan, Rizvana Ahmad, Tamas Hickish, Stephen Houston, Daniel Rea, John Bartlett, Carlos Caldas, David Cameron, Larry Hayward. ARTemis: A randomised trial of bevacizumab with neo-adjuvant chemotherapy for patients with HER2-negative early breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD2-3.

Purpose Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) for breast cancer (BC) is a prognostic factor for relapse-free and overall survival (OS). Despite recent therapeutic developments for early BC, there are still a significant proportion of patients who do not achieve pCR. In this study we established pCR rates in routine care and investigated possible predictive factors of pCR, including HER2 status. Methods We evaluated 980 stage I-III BC patients receiving NACT between 2013 and 2022. Patient characteristics, rates of pCR (ypT0-is ypN0), toxicities, treatment modifications and survival outcomes were recorded. Standard histopathological variables were recorded [with HER2-low status, defined as HER2 1+ on immunohistochemistry (IHC) or 2+ on IHC without in situ hybridization (ISH) gene amplification]. Overall survival (OS) and relapse-free survival (RFS) were calculated. Median follow-up time was 60.3 months (interquartile range 19.7-78.7). Results The mean age of the study population was 49.6 ± 11.2 years. 64% had stage II disease, 70.5% had grade 3 disease, and 90.5% had ductal histopathology. 34.6% had estrogen receptor (ER)-positive/HER2-negative, 27.1% had triple-negative (TN), and 38.3% had HER2-positive BC. 233 patients (23.8%) had HER2-low disease. pCR rate was 35.8% in the overall population, 16.8% in ER-positive/HER2 negative BC, 32.7% in TNBC and 55.2% in HER2-positive BC. pCR rate differed according to grade, histology, HER2 status, radiological and clinical response of disease (p < 0.001) and early discontinuation of NACT (p = 0.001), but not according to age, menopausal status, BRCA status, platinum use, NACT dose reduction or delays, neutrophils-to-lymphocytes, platelets-to-lymphocytes, or lymphocytes-to-monocytes ratios. OS and RFS were better following pCR [HR 0.23 (95% CI, 0.14-0.38, p < 0.001) and HR 0.27 (95% CI, 0.18-0.40, p < 0.001), respectively]. Among HER2-negative BC patients (605, 61.7% of the entire cohort), there was a trend to lower pCR rate in HER2-low compared to HER2-negative (IHC 0) BC (19.7% vs 26.3% respectively, p = 0.06). pCR rate was significantly lower in ER-positive/HER2-low compared to ER-positive/HER2-negative (IHC 0) BC (12.1% vs 20.9% respectively, p = 0.031), while no difference in pCR rates was observed in TNBC patients by HER2 status. Despite a lower rate of pCR, Kaplan-Meyer curve showed that OS was significantly better in the HER2-low BC compared to HER2-negative (IHC 0) population at 100-months follow up. Multivariable Cox-regression model in the HER2-negative BC cohort demonstrated that HER2-low status was an independent predictor of OS (HR 0.59, 95% CI, 0.39-0.89 p = 0.012). Conclusions In our real-world analysis, pCR rates are consistent with the published data. Many patients still have residual disease following NACT, predicting worse outcomes, and may benefit from further adjuvant systemic therapies. Consistent with other studies, our findings suggest a possible prognostic and predictive role of HER2-low status especially among patients with ER-positive BC. This could lay the foundations for novel therapies targeting HER2 among HER2-low cancer subtypes. Citation Format: Matilde Corianò, Nicolo M.L. Battisti, Hala Aziz, Nalinie Joharatnam Hogan, Antonino Musolino, Alistair Ring. Pathological complete response to neoadjuvant systemic therapy and its predictive factors among early breast cancer subtypes: the emerging role of HER2 [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 PO2-02-09.

LBA1 Background: PARP inhibitors (PARPi) target cancers with homologous recombination repair defects by synthetic lethality. The PARPi olaparib (OL) is licensed for metastatic HER2-negative breast cancer with BRCA1/2 germline mutation (gBRCAm). Despite (neo)adjuvant chemotherapy ([N]ACT), recurrence rates in patients (pts) with gBRCAm early breast cancer (EBC) can be high. Novel adjuvant treatments are needed. Methods: OlympiA (NCT02032823), a randomized, double-blind, phase III study, enrolled pts with gBRCAm and HER2-negative (TNBC or hormone-receptor+ [HR+]) high-risk EBC after primary local treatment and ACT/NACT. Eligible pts with TNBC had ≥pT2 or ≥pN1 disease prior to ACT or non-pCR after NACT; those with HR+ BC had ≥4 positive nodes prior to ACT or non-pCR and CPS&EG score ≥3 after NACT. Pts were randomized 1:1 to 1 year of continuous oral OL (300 mg BID) or placebo (PL). Endocrine therapy and bisphosphonates were allowed. The primary endpoint was invasive disease-free survival (IDFS) in the ITT population. Secondary endpoints included distant DFS (DDFS), overall survival (OS) and safety. Safety analysis included adverse events of special interest (AESI) (myelodysplastic syndrome/ acute myeloid leukemia, new primary malignancy, pneumonitis). Per protocol IDMC interim analysis (IA) review was triggered at 165 IDFS events in the first 900 pts, with superiority boundaries based on a hierarchical multiple testing procedure: P < 0.005 for IDFS, followed by P < 0.005 for DDFS and p<0.01 for OS. Results: 1836 pts were enrolled between 06/14–05/19; 49.9% had ACT, 50.1% NACT. Baseline demographics and tumor characteristics were balanced between arms. 82.2% had TNBC; 26.5% received a platinum agent. The IDMC recommended data unblinding as IA showed a significant benefit of OL vs PL for IDFS (hazard ratio [HR] 0.58; 99.5% CI 0.41, 0.82; P < 0.0001) at 2.5 yrs median follow-up. IDFS events occurred in 106/921 and 178/915 pts assigned to OL and PL, respectively. 3-yr IDFS was 85.9% vs 77.1% (diff. 8.8%; 95% CI 4.5%, 13.0%). DDFS was significantly improved with OL (HR 0.57; 99.5% CI 0.39, 0.83; P< 0.0001); 3-yr DDFS was 87.5% vs 80.4% (diff. 7.1%; 95% CI 3.0%, 11.1%). OS was greater for OL than PL but was not statistically significant at IA (HR 0.68; 99.0% CI 0.44, 1.05; P = 0.024); 3-yr OS% 92.0% vs 88.3% (diff. 3.7%; 95% CI 0.3%, 7.1%). Median intended OL exposure was 94.8%. AEs were consistent with the label. G3+ AEs in >1% of OL pts were; anemia (8.7%), neutropenia (4.8%), leukopenia (3.0%), fatigue (1.8%), and lymphocytopenia (1.2%). SAEs and AESI were not increased by OL, SAE 8.7% vs 8.4% and AESI 3.3% vs 5.1%, OL vs PL respectively. Conclusions: Adjuvant OL following ACT or NACT significantly improved IDFS and DDFS with acceptable toxicity in pts with gBRCAm and high-risk HER2-negative EBC. Clinical trial information: NCT02032823.

Background: The presence of CTC in metastatic BC is associated with an impaired prognosis. Recent data show a reduced disease-free survival and increased risk of death in the presence of CTC in EBC. Therefore, patients with persisting CTC after (neo)adjuvant chemotherapy might benefit from additional systemic treatment. Recent data have reinforced the hypothesis that trastuzumab can eliminate tumor cells by antibody dependent cell cytotoxicity (ADCC) or other immune mechanisms. Preclinical data have provided evidence that the benefit of trastuzumab may be associated with targeting cancer stem cells in a HER2 independent model (Ithimakin et al Cancer Res 2013). Trastuzumab eliminated CTC, irrespective of the HER2 status of the primary tumor and of CTC and this was associated with reduced relapses(Georgoulias et al Ann Oncol 2012). Trial Design: Treat CTC trial is a multicenter European randomized phase II trial, sponsored by the EORTC and run under the BIG umbrella. It will assess the efficacy of trastuzumab in eliminating persisting CTC after the completion of (neo)adjuvant chemotherapy and surgery in patients with HER-2-negative EBC. Eligible patients will be randomized in a 1:1 ratio to either 6 cycles of trastuzumab or observation. Patients’ peripheral blood will be tested again for CTC after 18 weeks. Main Eligibility criteria: - Adequately excised HER2-negative EBC - Evidence of CTC detection using the CellSearch technology after completion of (neo)adjuvant chemotherapy - Completion of adjuvant chemotherapy for node-positive disease or neoadjuvant chemotherapy with residual invasive disease in breast or lymph nodes (no complete pathological response) - Histological Grade > 1 and primary tumor size > 1 cm Specific aims: The primaryobjective of the trial is to evaluate whether trastuzumab decreases the detection rate of CTC in patients with HER2-negative EBC by comparing the trastuzumab treated arm to the observation arm. Furthermore, clinical outcomes as measured by Recurrence Free Interval (RFI), Invasive Disease Free Survival (IDFS), Disease Free Survival (DFS) and Overall Survival (OS)) between the trastuzumab and observation arms will be compared. Present accrual and target accrual: Treat CTC started patient screening in April 2013 in Belgium. It is estimated that 2175 women will be registered to include 174 patients eligible for randomization. Accrual is expected to be completed in 2 years. Methods: The primary test will be a one-sided test to compare the trastuzumab arm to the observation arm for the CTC detection rate at week 18 (superiority test). The comparison for the primary endpoint will be performed on the intention-to-treat population using a one-sided test with overall a of 0.1. The odds ratio and its confidence interval will be estimated using a logistic regression model. The comparison of RFI, IDFS, DFS and OS will be done using a two-sided test in a proportional hazards model for cause specific hazard, adjusted for the stratification factors. Perspectives: Given the prognostic relevance of CTC in BC, the Treat CTC trial will be the first multicenter, randomized trial in which CTC are used to guide treatment decisions in EBC. The results of this trial will help to clarify the clinical utility of CTCs in early disease. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT1-3-02.

BACKGROUND: Abnormalities of the PI3kinase/AKT/mTOR signaling network are common in breast cancer (BC) and are associated with endocrine resistance. Everolimus, an mTOR-inhibitor increased PFS when combined with endocrine therapy (ET) in the metastatic setting and is thought to revert endocrine resistance. S1207 is a phase III randomized, placebo-controlled trial evaluating the role of everolimus in combination with ET in the adjuvant setting among patients with high-risk hormone receptor-positive, HER2-negative BC (NCT01674140). METHODS: Eligible patients were >18 years of age with histologically confirmed invasive hormone receptor-positive and HER2-negative high-risk BC. Four risk groups were defined as: 1) > 2cm node-negative disease (or pN1mi), and either an Oncotype DX® Recurrence Score (RS) > 25 or MammaPrint® high-risk category (MP high); 2) 1-3 positive nodes and either RS >25, MP high or a pathological grade 3 tumor; 3) >4 positive lymph nodes. Patients treated with neoadjuvant chemotherapy were eligible if: 4) after surgery had >1 lymph node involvement. Patients were randomized 1:1 to physician’s choice adjuvant ET in combination with one year of everolimus (10 mg PO daily) or ET plus placebo stratified by risk group. The primary endpoint was invasive disease-free survival (IDFS) evaluated by a stratified log-rank test. Secondary endpoints included overall survival (OS) and safety. The hazard ratio (HR) for treatment efficacy was estimated using Cox regression with stratification by risk groups. Subset analyses included preplanned evaluation within risk group and exploratory analyses of menopausal status and age. RESULTS: 1,939 patients were randomized between September 2013 and May 2019, of them 1,792 were eligible and included in the analysis (896 per arm). Primary reason for ineligibility was timing after chemotherapy/radiation or not high risk. Median age was 54 years (22-85) and 32% were premenopausal. With a median follow-up of 50.5 months, there were 389 IDFS events as of May 2022 (data cutoff). 5-year IDFS was 74.8% among patients treated with everolimus and 73.9% among patients treated with placebo, HR=0.93 (95% CI 0.76-1.14). However, the proportional hazards assumption was violated (p=0.02) suggesting differential treatment effect over time. The HR during the one year of treatment was 0.72 (95% CI 0.47-1.10) while after one year it was 1.00 (95% CI 0.80-1.26). The 5-year OS was 87.6% in the everolimus arm and 85.5% in the placebo arm, HR=0.98 (95% CI 0.75-1.28). Analysis by risk group did not show higher everolimus benefit as risk increased. No difference in IDFS or OS was seen among postmenopausal patients (IDFS HR=1.08 [95% CI 0.85-1.36], OS HR=1.19 [95% CI 0.87-1.61]). Among premenopausal patients, everolimus was associated with improved IDFS (HR=0.63 [95% CI 0.43-0.93]) and OS (HR=0.48 [95% CI 0.26-0.88]). Treatment completion of randomized therapy was lower in the everolimus arm compared to placebo (47.9% v 72.7%). Grade 3 and 4 toxicities were noted in 6.5% and 0.5% of patients in the placebo arm and in 31.2% and 3.7% in the everolimus arm respectively. CONCLUSIONS: Addition of one year of adjuvant everolimus to standard adjuvant ET did not improve IDFS or OS and was associated with low completion rate and increased AEs. Among premenopausal patients there was a benefit in IDFS and OS that is hypothesis generating. Future translational studies will evaluate potential predictors of everolimus benefit and drug toxicity. Citation Format: Marianna Chavez, Jieling Miao, Lajos Pusztai, Matthew P. Goetz, Priya Rastogi, Patricia A. Ganz, Eleftherios (Terry) Mamounas, Soonmyung Paik, Hanna Bandos, Wajeeha Razaq, Anne O’Dea, Virginia Kaklamani, Andrea L.M. Silber, Lisa E. Flaum, Eleni Andreopolu, Joseph Baar, Albert G. Wendt, Jennifer F. Carney, Priyanka Sharma, Julie R. Gralow, Danika L. Lew, William E. Barlow, Gabriel N. Hortobagyi. Results from a phase III randomized, placebo-controlled clinical trial evaluating adjuvant endocrine therapy +/- 1 year of everolimus in patients with high-risk hormone receptor-positive, HER2-negative breast cancer: SWOG S1207 [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 GS1-07.

Background: Women with early-stage breast cancer (eBC) who have inherited BRCA1 or BRCA2 mutations (gBRCAm) are typically diagnosed at a younger age and often require more intensive treatment. In the randomized, double-blind OlympiA trial of HER2-negative (HER2–) gBRCAm patients, olaparib, a targeted poly (ADP-ribose) polymerase inhibitor (PARPi), significantly improved invasive disease free survival (IDFS), distant disease free survival (DDFS) and overall survival (OS) and was subsequently approved for adjuvant treatment of gBRCAm HER2– high-risk eBC patients. This study examined the real-world patient characteristics, treatment patterns and clinical outcomes by gBRCA status among patients with HER2– eBC in a US community oncology setting prior to olaparib US approval for treatment of eBC. Methods: This retrospective observational study used chart review data from The US Oncology Network's iKnowMed database to examine adult patients diagnosed with HER2– eBC (stage I-III) initiating systemic neoadjuvant or adjuvant therapy with chemotherapy and/or endocrine therapy between January 1, 2012 and December 31, 2018. Patients with valid gBRCAm test results (all gBRCAm and randomly selected BRCAwt patients) were included and followed through December 31, 2021. Patients were excluded if they had HER2+ tumors and progressed to stage IV within 6 months after initiation of neoadjuvant therapy or were diagnosed with another primary cancer. Descriptive analyses assessed patient characteristics. Kaplan Meier methods and multivariate Cox proportional hazard models (CPHM) were used to evaluate IDFS, DDFS and OS by gBRCA status and by HR+/HER2– or TNBC eBC subsets. Results: Among 298 BC patients meeting initial criteria, 42% had gBRCAm (n=124, 43% hormone receptor positive [HR+], 56% triple-negative BC [TNBC], 1% unknown), and 58% had gBRCAwt (n=174, 74% HR+, 22% TNBC). Median (interquartile) age at surgery was numerically lower in gBRCAm (45 [36,55] years) than gBRCAwt (48 [41,55] years) patients. A numerically higher proportion of gBRCAm patients received neoadjuvant therapy compared with gBRCAwt (Neoadj: gBRCAm 37.1% vs gBRCAwt 12.6%) but the reverse was true for adjuvant (Adj: gBRCAm 42.7% vs gBRCAwt 65.5%) and neoadjuvant + adjuvant use was numerically similar (Neoadj+Adj: gBRCAm 20.1% vs gBRCAwt 21.8%). The majority of TNBC patients received neoadjuvant therapy while the majority of HR+ patients received adjuvant therapy (Neoadj: TNBC 51.4% vs HR+ 6.6%, Adj: TNBC 29.0% vs HR+ 71.4%, Neoadj+Adj: TNBC 19.6% vs HR+ 22.0%). Median IDFS, DDFS, and OS in both study cohorts were not reached. Median follow-up from surgery was < 5 years (overall 59.0 months; gBRCAm 50.6 months; gBRCAwt 61.3 months). At 60 months, in gBRCAm and gBRCAwt respectively, estimated IDFS were 85.5% and 90.9%, estimated DDFS 88.1% and 92.2%, and estimated survival 91.9% and 95.2%. At 60 months, in HR+/HER2– and TNBC respectively, estimated IDFS were 92.4% and 81.2%, estimated DDFS 93.9% and 85.7%, and estimated survival 96.3% and 90.9%. CPHM results showed that risks of invasive disease (HR 1.74; 95% CI 0.83-3.64; p=0.15), distant disease (HR 1.24; 95% CI 0.50-3.07; p=0.65) and death (HR 1.79; 95% CI 0.52-6.13; p=0.353) were similar between gBRCAm and gBRCAwt patients. Between HR+/HER2– and TNBC patients, risks of invasive disease (HR=0.63; 95% CI 0.21-1.89; p=0.41), distant disease (HR=0.42; 95% CI 0.11-1.67; p=0.22) and death (HR 0.48; 95% CI 0.09-2.70; p=0.41) were similar. Conclusions: This real-world chart review study of data through 2021 (before PARPi approval for eBC) with limited follow up of 5 years found that gBRCAm patients had a numerically shorter survival (IDFS, DDFS and OS) than gBRCAwt, but this difference was not statistically significantly different. Given that the follow-up period was too short to draw conclusions, further studies examining clinical outcomes over a longer follow-up period after approval of PARPi may be of interest. Citation Format: Jay Andersen, Jagadeswara Earla, Nicole Fulcher, Juliet Ndukum, Nicholas J Robert, Mark Robson, Weiyan Li, Jaime Mejia. Real world treatment patterns and clinical outcomes by germline BRCA (gBRCA) mutation status in patients with HER2-negative early breast cancer in the US community oncology setting: a retrospective observational chart-review study [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 PO2-17-06.

Background: Adjuvant (adj) endocrine therapy (ET) is the mainstay treatment (tx) for estrogen receptor-positive, HER2-negative early breast cancer (ER+ HER2- eBC). However, up to 1/3 of patients (pts) eventually experience recurrence. Clinically, there is an unmet need for more tolerable and efficacious ET to improve adherence and pt outcomes. Giredestrant, a next-generation oral selective estrogen receptor antagonist and degrader (SERD), was shown to be more potent than other SERDs (Liang 2021; Bardia 2023) and demonstrated superior antiproliferative activity vs anastrozole in the neoadj coopERA BC trial (Hurvitz 2023). Results of the prespecified interim analysis of the global, randomized lidERA BC trial (NCT04961996) are presented. Methods: Pts with Stage I-III ER+ HER2- eBC were randomized 1:1 to giredestrant 30 mg oral daily (with an LHRH agonist in pre- and peri-menopausal women, and men) or standard-of-care ET (tamoxifen or aromatase inhibitor) for 5 years (yr). The primary endpoint was invasive disease-free survival (IDFS). Key secondary endpoints were overall survival (OS), distant recurrence-free interval (DRFI), and safety. Results: 4170 pts were randomized (Aug 2021-Sep 2023): 2084 to giredestrant; 2086 to standard-of-care ET. Median age was 54.0 yr; 59.3% of pts were postmenopausal; 13.0%, 47.4%, and 39.6% had Stage I, II, and III BC, respectively. Median follow-up at clinical cutoff (Aug 8, 2025) was 32.3 months, with 336 IDFS events. Efficacy is shown in the table. Giredestrant demonstrated superior IDFS vs standard-of-care ET (hazard ratio [HR] 0.70; 95% confidence interval [CI], 0.57, 0.87; p = 0.0014). 3-yr IDFS rates were 92.4% and 89.6%, respectively. There was a trend towards OS improvement in the giredestrant arm vs the standard-of-care ET arm (HR 0.79; 95% CI, 0.56,1.12). The DRFI HR was 0.69 (95% CI, 0.54, 0.89). The most common adverse events (AEs) in the giredestrant vs standard-of-care ET arms, respectively, were arthralgia (48.0% vs 47.1%), hot flush (27.4% vs 28.8%), and headache (15.3% vs 13.2%); the most common Grade 3-4 AEs, hypertension (2.6% vs 2.0%) and arthralgia (1.5% vs 1.8%). Discontinuations due to AEs occurred in 5.3% with giredestrant vs 8.2% with standard-of-care ET. Conclusions: lidERA BC is the first Phase III trial to demonstrate benefit with an oral SERD in eBC. Giredestrant tx resulted in a statistically significant and clinically meaningful IDFS improvement vs standard-of-care ET in ER+, HER2- eBC. OS trended in favor of the giredestrant arm, and DRFI was improved vs standard-of-care ET. The safety profile was favorable and consistent with known profiles, and the discontinuation rate was slightly lower with giredestrant compared with standard-of-care ET. Overall, the results support giredestrant as a potential new standard for pts with HR+ eBC. Citation Format: A. Bardia, P. Schmid, M. Martín, S. Hurvitz, K. Jung, M. Rimawi, S. Saji, G. Werutsky, N. Harbeck, S. Loi, A. Ogiya, M. Ruiz-Borrego, A. Alacacıoğlu, J. Wu, C. Ye, M. Liste-Hermoso, N. Withana, T. Badovinac Crnjevic, M. Shah, P. Pérez-Moreno, C. Geyer, Jr.. Giredestrant vs standard-of-care endocrine therapy as adjuvant treatment for patients with estrogen receptor-positive, HER2-negative early breast cancer: Results from the global Phase III lidERA Breast Cancer trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr GS1-10.

Background: Overexpression of HER2 is a significant prognostic and predictive factor in early breast cancer. HER2 positive tumors are those scored by immunohistochemistry (IHC) 3+ or 2+ with amplification by in situ hybridization (ISH). These tumors may benefit from HER2-targeted treatment and additionally, in early HER2-positive BC, achieving a complete pathological response after neoadjuvant treatment improves patient survival. In recent years, new anti-HER2 antibody-drug conjugates have proven effective for HER2 low BC (defined as IHC score 1+ or 2+ not amplified) in the metastatic disease setting; however, in HER2-low early BC, studies testing novel anti-HER2 antibody-drug conjugates as neoadjuvant therapy (NAT) are ongoing. Currently, we don´t know exactly whether HER2 expression can influence the pathological response rate after NAT or disease-free survival (DFS) in these patients compared to HER2-zero (IHC 0). The aim of our study is to determine the impact on response rate to NAT and survival outcomes in early HER2-negative BC. Methods: We conducted a retrospective study in two hospitals in Andalucia, Spain. Patients with early HER2 negative BC treated with NAT from January 2015 to June 2022 were included. Patients were divided into HER2 low patients (IHC 1+ or 2+ not amplified) and HER2 0 (IHC 0). We collected clinical and pathological characteristics, pathological response rate using the Residual Cancer Burden (RCB) system where a complete pathological response (pCR) was defined as ypT0/ypTis and ypN0, and survival outcomes. The primary objective of the study was to analyze the pCR rate after NAT according to HER2 score, and secondary objectives were to assess disease-free survival and overall survival (DFS and OS rates). Results: 574 patients were included (100% women). 397 patients had hormone receptors (luminal BC) on these tumors, and 177 did not have them, i.e., triple-negative BC (TNBC). 225 patients were HER2-zero, and 312 patients were HER2-low (253/312 patients had luminal BC and 59/312 patients were TNBC). The pCR in HER2-low patients was 17.3% and 23.1% in HER2-zero patients (p=0.047). For luminal BC patients, the pCR was 16.7% in HER2-low tumors and 13.7% in HER2-zero tumors (p=0.29). Similarly, there was no difference in pCR rates in TNBC patients (45.8% in HER2-low and 53.8% in HER2-zero tumors, respectively, (p=0.958). The overall survival (OS) at 96 months was 88.7% (95% CI 85.6%-92%). Regarding survival outcomes, neither HER2 expression level was associated with higher 8-year DFS: 81.1% in HER2-low patients (95% CI 75.7%-86.8%) and 74.9% in HER2-zero patients (95% CI 62.3%-90.1%) p=0.64. There was no difference between histological subtypes at 8-years regarding DFS rate: 80.5% (95% CI 74.3%-87.2%) in luminal HER2-low patients and 76.3% (95% CI 60.8%-95.7%) in luminal HER2-zero patients, p=0.22; 83.8% in TNBC HER2-low (95% CI 74.5%-94.2%) and 77.5% in TNBC HER2-zero patients (95% CI 69.4%-86.6%) p=0.26. We also didn´t find significant differences in terms of OS. For HER2-low patients, the 8-year OS was 90.9% (95% CI 87%-94.9%) and for HER2-zero patients, it was 86.4% (95% CI 80.8%- 92.5%) p=0.46. There were also no differences in OS for different histological subgroups with an 8-year OS in luminal HER2-low breast cancer patients of 92.5% (95% CI 88%-96.7%) and 87% in HER2-zero (95% CI 78.9%-96.1%) p=0.91. In patients with triple-negative breast cancer phenotype, the OS was 84.2% for HER2-low (95% CI 74.5%-95.2%) and 85.3% for HER2-zero (95% CI 77.9%-93.4%) p=1. Conclusions: We found no difference in survival outcomes and response rate to conventional NAT between HER2-low and HER2-zero expression levels. Therefore, our data do not support the hypothesis of HER2-low as a biologically specific breast cancer subtype. Further research on this approach with HER2 antibody-drug conjugate schemes as an alternative to traditional NAT schemes is warranted. Citation Format: Ana Gil-Torralvo, Yeray Rodriguez, Alejandro Falcon, David Morales, Mónica Cejuela, Isabel Miras, Marta Amérigo, Manuel Ruíz - Borrego, Juan Bayo, Francisco Javier Salvador Bofill. Is HER2-low a biologically distinct breast cancer (BC) subtype? Prognosis and pathological complete response rate after neoadjuvant treatment (NAT) in early breast cancer (BC) HER2 negative [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 PO1-27-07.