Neoadjuvant Systemic Therapy Research Articles

Treatment Outcomes Evaluation in Breast Cancer Patients with a Pathological Complete Response after Neoadjuvant Systemic Therapy Depending on Different Types of Local Treatment

Treatment Outcomes Evaluation in Breast Cancer Patients with a Pathological Complete Response after Neoadjuvant Systemic Therapy Depending on Different Types of Local Treatment

Abstract PO5-18-10: Omission of SLNB in triple-negative and HER2-positive breast cancer patients with radiologic and pathologic complete response in the breast after NAST: a single-arm, prospective surgical trial (EUBREAST-01 trial, GBG 104)

Abstract Background: Currently, axillary surgery for breast cancer is considered a staging procedure that does not seem to influence breast cancer mortality since the risk of developing metastasis depends mainly on the biological behavior of the primary (seed-and-soil model). Based on this, postsurgical therapy should be considered based on biological tumor characteristics. Retrospective data of cancer registry trials showed a strong correlation between breast pathologic complete response (pCR) and nodal pCR depending on intrinsic subtypes. Improvements in systemic treatments for breast cancer have increased the rates of pCR in patients receiving neoadjuvant systemic therapy (NAST), offering the opportunity to decrease, and perhaps eliminate, surgery in patients who have a pCR. Trial design: The EUBREAST network designed a clinical trial (NCT04101851) in which only patients with the highest likelihood of having a pCR after NAST (triple-negative or HER2-positive breast cancer) will be included, and type of surgery will be defined according to the response to NAST rather than on the classical T and N status at presentation. In the ongoing trial, axillary surgery will be eliminated (no axillary sentinel lymph node biopsy [SLNB]) for initially clinical node-negative (cN0) patients with radiologic complete remission (rCR) and a breast pCR (ypT0/ypTis) as determined in the lumpectomy specimen. The trial design is a multicenter single-arm study with a limited number of patients (N=440 as the screening population with an expected 80% pCR-rate) which might give practice-changing results in a short period, sparing the time and the costs of a randomized comparison. Patients will be recruited in European countries (Austria, Germany, Italy, and Spain) over 48 months. Inclusion criteria: -Written informed consent -Histologically confirmed unilateral primary invasive carcinoma of the breast (core biopsy). Multifocal or multicentric tumors are allowed if breast-conserving surgery (BCS) is planned. -Age at diagnosis at least 18 years -imaging techniques with estimated tumor stage between cT1-T3 before NAST -triple-negative (TNBC) or HER2-positive invasive breast cancer -TNBC is defined by: ER-negative (< 10% positive cells in IHC) and PgR-negative (< 10% positive cells in IHC), HER2-negative -clinically and sonographically tumor-free axilla before core biopsy (cN0/iN0) -in cases with cN0 and iN+, a negative core biopsy or fine-needle aspiration biopsy of the sonographically suspected lymph node is required -no evidence for distant metastasis (M0) -standard NAST with rCR -planned BCS with postoperative external whole-breast irradiation (conventional fractionation or hypofractionation) Primary objective: 3-year rate of axillary recurrence-free survival (ARFS) after BCS Statistics: The calculated total case number for per-protocol analysis is N=350, and the expected total number of screened patients is N=440. The assumption for acceptable 3-year ARFS ≥98.5% in the experimental arm is based on previous study findings. Timelines: -First patient in: January 2021 -Last patient in: December 2024 -Primary outcome analysis: Q1/2027 Current accrual: In June 2023, 255 patients were recruited; the majority of them in Germany. Contact: Prof. Dr. Toralf Reimer (eubreast-01@kliniksued-rostock.de), study chair Dr. Oreste D. Gentilini (gentilini.oreste@hsr.it), study co-chair Funding by Else Kroener-Fresenius Foundation, German Society of Senology, University of Rostock (Germany), and San Raffaele Hospital (Milan, Italy). Citation Format: Toralf Reimer, Bernd Gerber, Thorsten Kuehn, Nikola Bangemann, Anke Kleine-Tebbe, Andrea Stefek, Ulrike Doerste, Carolin Hammerle, Oliver Hoffmann, Alexander Hein, Isabel Rubio, Florentia Peintinger, Keyur Mehta, Sibylle Loibl, Edoardo Botteri, Oreste Gentilini. Omission of SLNB in triple-negative and HER2-positive breast cancer patients with radiologic and pathologic complete response in the breast after NAST: a single-arm, prospective surgical trial (EUBREAST-01 trial, GBG 104) [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 PO5-18-10.

Abstract PO2-23-06: Clinical study of stained region lymph node biopsy (SrLNB) in axillary surgery after neoadjuvant systemic therapy in patients with axillary lymph node positive breast cancer

Abstract Background The probability of axillary lymph node converting from positive to negative after neoadjuvant systemic therapy (NST) for breast cancer patients is approximately 40%. A variety of axillary lymph node biopsy surgeries based on sentinel lymph node biopsy (SLNB) can help to omit axillary lymph node dissection (ALND). The common disadvantages, however, are mainly the restrictions, such as the need for strict regulation of the use of radiotracers, the high number of retrieved lymph nodes required, and the need to purchase ancillary equipment. The more restrictions there are, the more they limit the spread and availability of the technique and, more importantly, reduce the number of patients who will benefit. In fact, for patients with metastatic lymph nodes, the sentinel lymph nodes must be included in the lymph nodes that have metastasized. If these metastatic lymph nodes can be accurately marked and precisely retrieved after NST, it is possible to assess whether the axillary lymph nodes are converted from positive to negative without the need for SLNB. Materials and methods Breast cancer patients with pathologically confirmed axillary lymph node metastases who were receiving NST were recruited for this study. Before NST, carbon nanoparticles suspension injections were injected into the cortex of the pathologically confirmed metastatic lymph node to stain the region where the metastatic lymph node was located. The lymph nodes in the stained region were retrieved by stained region lymph node biopsy (SrLNB) during the axillary surgery, followed by ALND, without the use of SLNB. Finally, the identification rate and false-negative rate (FNR) of SrLNB were statistically analyzed according to pathology data. Results A total of 159 patients were successfully enrolled in this study between September 24, 2020 and December 2, 2022, with an axillary pCR rate of 40.9% (65/159). The identification rate of SrLNB was 100% (159/159), with an overall FNR of 5.3% (5/94). Subgroup analysis revealed that in the subgroups of 1, 2, 3 and ≥4 SrLN, the FNR was 0%, 0%, 0% and 8.9% (5/56), respectively, whereas in the cN1, cN2 and cN3 subgroups the FNR was 7.7% (3/39), 2.6% (1/38) and 5.9% (1/17), respectively. The FNR indexes were within the safety threshold of 10% in all subgroups. Conclusion SrLNB has a high identification rate and a low FNR and is useful for screening patients with positive to negative axillary lymph nodes for omitting ALND. srLNB requires only the use of an affordable and radiation-free carbon nanoparticles suspension injection for marking, making the whole technique simpler and easier to disseminate. The data from this study also suggest that SLNB may not be mandatory for axillary biopsy in patients with positive axillary lymph nodes undergoing NST. Table 1. General characteristics of enrolled patients. Table 2. Analysis of factors affecting axillary pCR rates. Table 3. Analysis for the FNR of SrLNB. Citation Format: Jue Wang, Rui Chen, Cuiying Li, Hailing Zha, Qiannan Zhu, Lifeng Huang, Xiaoming Zha. Clinical study of stained region lymph node biopsy (SrLNB) in axillary surgery after neoadjuvant systemic therapy in patients with axillary lymph node positive 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 PO2-23-06.

Abstract PO5-03-06: Optimizing therapeutic regimens via digital twins to improve triple negative breast cancer response to neoadjuvant therapy

Abstract Introduction: Neoadjuvant systemic therapy (NAT) has been the standard-of-care of stage II-III, locally advanced triple-negative breast cancer (TNBC). However, about 50% of TNBC patients achieve a pathological complete response (pCR) to conventional neoadjuvant chemotherapy (NAC)1. Recently approved combination of NAC with the immunotherapy pembrolizumab, has improved the pCR rate by 7.5%2, although with a 44% risk of immune-related adverse reaction3. Aside from the need to develop new therapies with higher efficacy and lower toxicity, a critical barrier to improving TNBC response is the lack of rigorous ways to personally tailor therapeutic regimens. We seek to address this challenge by employing digital twins (i.e., mathematical models that provide virtual representation of individual patients and predict the changes at future time points) to systematically evaluate individual TNBC patient’s response to different NAT regimens, thereby patient-specifically optimizing treatments. Methods: A TNBC cohort (n = 139) from the ARTEMIS trial (NCT02276433)4 was used for this study. All patients received 4 cycles of Adriamycin/Cytoxan (A/C) every 2 weeks, followed by 12 cycles of weekly Taxol or experimental therapy in Phase II trials. All patients had surgery after NAT and post-surgical pathology to assess response status. For each patient, longitudinal MRIs were collected before, during, and after A/C. We have developed digital twins to integrate the longitudinal MRIs with a mechanism-based model to accurately predict TNBC response5. The model was based on a reaction-diffusion equation that describes the change in tumor cellularity due to migration, proliferation, and drug-induced death. With parameters personalized using MRIs, the patient-specific model (i.e., digital twin) significantly improved the accuracy to predict pCR5. We investigated patient-specific treatment optimization on 37 (19 pCR, 18 non-pCR) chemo-sensitive patients (≥ 70% volume decrease after A/C) who received only NAC. We evaluated the effect of altering the A/C/Taxol schedules on patient response. Specifically, each patient’s digital twin was used to predict the patient’s response to 128 clinically reasonable schedules of A/C/Taxol; i.e., 8 candidate A/C schedules combining with 16 candidate Taxol schedules (Table 1). The predicted response (pCR or non-pCR) from each alternative schedule was compared to the patient response from the actual treatment. Results: Without changing the total dose, shortening the duration of A/C/Taxol administration increased the treatment efficacy. The effectiveness of altering the schedules varied substantially in different patients. In particular, 8 patients who had non-pCR responses to their actual treatment were predicted to achieve pCR with the dense-dose Taxol (i.e., 4 cycles Taxol, 2 weeks per cycle), indicating a 21.62% improvement of pCR rate in the cohort. Discussion and conclusion: The preliminary results with our digital twin approach provided a unique opportunity of improving TNBC response to NAT through patient-specific optimization of therapeutic schedules. The ongoing effort focuses on accounting for toxicity and investigating the effects of altering therapy types and doses in combination with the schedules on the patient response. [1] Spring et al., Clin Cancer Res, 2020. [2] Schmid et al., NEJM, 2022. [3] Shah et al., Clin Cancer Res, 2022. [4] Yam et al., Clin Cancer Res, 2021. [5] Wu et al., Cancer Res, 2022. Table 1. Candidate therapeutic schedules Citation Format: Chengyue Wu, Ernesto Lima, Casey Stowers, Zhan Xu, Clinton Yam, Jong Bum Son, Jingfei Ma, Gaiane Rauch, Thomas Yankeelov. Optimizing therapeutic regimens via digital twins to improve triple negative breast cancer response to neoadjuvant therapy [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 PO5-03-06.

Abstract PS16-09: Analysis of the Radiosensitivity Index/Genomic-Adjusted Radiation Dose (RSI-GARD) in Paired Pre- and Post-Treatment TNBC Samples: Implications for Biomarker-Guided Radiotherapy

Abstract Objectives: Adjuvant radiotherapy is an important component of curative treatment for triple-negative breast cancer (TNBC). While there are several accepted variations in nominal dose and fractionation, these regimens are generally felt to be radiobiologically equivalent. Molecular radiosensitivity biomarkers have the potential to allow tailoring of physical radiotherapy dose for individual patients. The Radiosensitivity Index (RSI)/Genomic-Adjusted Radiation Dose (GARD) is a gene expression signature that predicts intrinsic radiosensitivity across multiple malignancies, with initial studies demonstrating clinical utility of RSI-GARD in TNBC. Since most TNBC patients will receive neoadjuvant systemic therapy, we sought to understand how neoadjuvant therapy-induced molecular adaptations could alter intrinsic radiosensitivity and RSI-GARD. Methods: Total RNA was isolated from pre-treatment and paired surgical specimens (for patients with residual disease (RD)) from TNBC patients treated with chemotherapy on the NeoSTOP (NCT02413320) or chemoimmunotherapy on the NeoPACT (NCT03639948) neoadjuvant trials and was subjected to RNA exome sequencing. The RSI was calculated according to the published algorithm using normalized expression of the 10 genes in this signature (AR, JUN1, STAT1, PRKCB, RELA, ABL1, SUMO1, PAK2, HDAC1, and IRF1). The resulting RSI score was substituted as the surviving fraction (SF) using the linear quadratic model of radiation-induced cellular lethality assuming a fractional dose of 2.0 Gy and a constant β=0.05 Gy−2 to derive a patient-specific α, which is a coefficient modifying dose-dependent cellular lethality resulting from binary mis-repair of double-strand breaks (DSBs) arising from a single particle track. Results: Pre-treatment sequencing data were available for N=200 patients and the overall pathologic complete response (pCR) rate was 56.5%. Paired pre- and post-treatment sequencing data were available for N=58 patients (N=27 from NeoSTOP and N=31 from NeoPACT). One NeoPACT patient had a negative RSI, which led to an undefined α. Under the assumptions of the RSI-substituted LQ model, the median α/β ratio (reflecting sensitivity to fractionation) for all pre-treatment samples was 11.7 Gy. TNBC patients who achieved pCR had a significantly higher pre-treatment α (i.e., higher intrinsic radiosensitivity) compared to patients who had residual disease (P=0.04), and this trend was the same for patients treated with chemotherapy (P=0.31) or chemoimmunotherapy (P=0.05). Importantly, α did not change significantly between paired pre- and post-treatment samples (median change post- vs. pre-treatment=0.03 Gy−1 (range -0.25 to +0.24 Gy−1; P=0.26) in patients with RD, with no difference in subgroups treated with chemotherapy (P=0.99) or chemoimmunotherapy (P=0.10). Conclusions: We found that predicted intrinsic radiosensitivity using the RSI-GARD is associated with pathologic response to neoadjuvant systemic therapy, suggesting that this signature also predicts intrinsic chemosensitivity in TNBC patients. The modeled α/β ratio for all pre-treatment samples was 11.7 Gy, which is substantially higher than empirically determined α/β ratios in studies that were enriched for HR+/HER2- breast cancers. Globally, the RSI-GARD score was not impacted by neoadjuvant systemic therapy, with no significant change in the score in paired pre- and post-treatment samples. These results can inform future testing and implementation of RSI-GARD into prospective trials. Citation Format: Shane Stecklein, Julia White, Rachel Yoder, Joshua Staley, Zachary Schmitt, Anne O'Dea, Lauren Nye, Deepti Satelli, Gregory Crane, Rashna Madan, Maura O'Neil, Andrew Godwin, Harsh Pathak, Qamar Khan, Joyce O'Shaughnessy, Priyanka Sharma. Analysis of the Radiosensitivity Index/Genomic-Adjusted Radiation Dose (RSI-GARD) in Paired Pre- and Post-Treatment TNBC Samples: Implications for Biomarker-Guided Radiotherapy [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 PS16-09.

Abstract PO3-18-11: A011801 (CompassHER2 RD): Postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive breast cancer

Abstract Background: Patients with HER2+ early breast cancer (EBC) and invasive residual disease (RD) after neoadjuvant therapy (NAT) have a higher risk of relapse than patients who have a pathologic complete response (pCR). Escalation of therapy in patients with RD using post-neoadjuvant T-DM1 has become the new standard of care, leading to improved invasive disease-free survival (iDFS), but patients with estrogen receptor (ER)-negative or nodal RD have suboptimal outcomes, and central nervous system recurrences are a challenge. More effective treatment strategies are urgently needed. Alliance A011801 (CompassHER2 RD) is an escalation trial for patients with high-risk HER2+ RD after neoadjuvant systemic therapy, evaluating the addition of the HER2 selective tyrosine kinase inhibitor (TKI) tucatinib to post-neoadjuvant T-DM1. Methods: Eligibility and Intervention: Patients with high-risk HER2+ RD (i.e., ER-, node-positive, or both) after a predefined course of neoadjuvant HER2-directed treatment are randomized 1:1 to adjuvant T-DM1 + placebo, vs. T-DM1 and tucatinib with adjuvant RT +/- ET. Eligibility criteria include completion of ≥ 6 cycles of NAT, including ≥ 9 weeks of paclitaxel and trastuzumab +/- pertuzumab. All chemotherapy (CT) must be completed preoperatively unless participating in EA1181 (~15-30% will be participants in the CompassHER2 pCR de-escalation companion trial [NCT04266249]; these patients must receive postoperative CT to complete ≥ 6 cycles prior to enrollment on A011801). Patients who received prior HER2-targeted TKIs or antibody-drug conjugates are ineligible. Objectives: The primary objective is to determine if iDFS is improved with addition of tucatinib to T-DM1 in patients with HER2+ EBC with RD after neoadjuvant systemic therapy; secondary endpoints include overall survival, breast cancer free survival, distant recurrence-free survival, brain metastases-free survival and disease-free survival. Correlative objectives include the association of i) tumor infiltrating lymphocyte (TILs) levels in the primary tumor and RD with iDFS, ii) TILs with tucatinib benefit, iii) iDFS and circulating tumor cells (CTC) at serial timepoints and iv) the magnitude of benefit of tucatinib (iDFS) in patients with/without detectable pretreatment CTCs. Quality of life and pharmacokinetic endpoints are also being evaluated. Statistics: A011801 is a prospective, double-blind, randomized, phase III superiority trial; stratified by i) receipt of postoperative CT (Y/N), ii) hormone receptor-status (+/-), and iii) pathologic lymph node status (+/-). The study targets an absolute difference of 5% in iDFS (control vs. experimental arm 82% & 87%, HR = 0.7), with a two-sided alpha of 0.05 and power of 80%. The sample size is 981; target accrual = 1031 patients; activation and estimated completion dates are 01/6/21 and ~ 01/2028. Accrual as of 7/10/2023: 438 patients. Support: U10CA180821, U10CA180882; Seagen Inc; https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT04457596 Citation Format: Ciara O'Sullivan, Karla Ballman, Linda McCall, Tyler Zemla, Anna Weiss, Melissa Mitchell, Victoria Blinder, Nadine Tung, William Irvin, Myounghee Lee, Sailaja Kamaraju, Matthew Goetz, W. Fraser Symmans, Virginia Borges, Ian Krop, Ann Partridge, Lisa Carey. A011801 (CompassHER2 RD): Postneoadjuvant T-DM1 + tucatinib/placebo in patients with residual HER2-positive invasive 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 PO3-18-11.

Abstract PO3-03-11: Receptor discordance after neoadjuvant chemotherapy with pembrolizumab in early-stage triple-negative breast cancer

Abstract Background: Discordance in hormone receptor (HR) and/or HER2 status between matched primary tumors and residual specimens following neoadjuvant therapy is a known phenomenon. In the neoadjuvant setting, systemic treatment is primarily informed by the HR and HER2 status from the diagnostic biopsy. Current guidelines recommend additional adjuvant capecitabine and/or pembrolizumab and/or olaparib for patients with triple-negative breast cancer (TNBC) after neoadjuvant systemic therapy if residual disease is present at the time of surgery. Discordance in biomarker status between the initial diagnosis and residual cancer may impact postoperative systemic therapy recommendations. This study aims to investigate the discordance rate in HR and HER2 status after neoadjuvant chemotherapy (NAC) plus pembrolizumab in early-stage TNBC. Furthermore, given the emerging data in support of novel antibody-drug conjugates (ADCs) for HER2-low breast cancer, the prevalence of HER2-low disease following standard-of-care neoadjuvant therapy may have critical clinical importance. Methods: We performed a single-institution, retrospective study of early-stage TNBC patients diagnosed between February 1st, 2020 and December 1st, 2022 who were treated with neoadjuvant chemotherapy and pembrolizumab. Patients who had not undergone definitive surgery were excluded. Demographic information, clinical and pathologic characteristics, and treatment data were collected from an institutional database. Pathologic complete response (pCR) was defined as ypT0/Tis and ypN0. HR and HER2 status before and after neoadjuvant therapy were collected. This study was approved by an Institutional Review Board. Results: Among the 94 patients included the median age was 55 years (IQR 47.0-61.8). The majority of patients had invasive ductal carcinomas (90.4%), were clinical T2 stage (68.1%), and node negative (55.3%). On the core tumor biopsy, estrogen receptor (ER) was < 1% in 90 (95.7%) patients and 1-10% in 4 (4.3%) of patients. Progesterone receptor (PR) was < 1% in 91 (96.8%) of patients and 1-10% in 3 (3.2%) of patients. HER2 was 0 by IHC in 49 (52.1%) patients, 1+ in 30 (31.9%) patients, 2+ in 11 (11.7%) patients, and not performed in 4 (4.3%) patients. A pCR (ypT0/Tis ypN0) was achieved in 60 (63.8%) of the 94 patients. In the 34 patients with residual disease, 29 patients had ER status evaluated at the time of surgery. Of these patients, 4 had tumors with ER < 1% at baseline but >5% at surgery. 28 patients with residual disease had PR evaluated at the time of surgery. Of these patients, all had tumors with PR < 1% at the time of surgery. 28 patients had residual tumors with HER2 status evaluated at the time of surgery (table). Of these patients, 18 (64.3%) tumor specimens were HER2-ultra-low, 9 (32.1%) were HER2-low-positive, and 1 (3.6%) was HER2-positive. Conclusion: Receptor discordance from the time of initial biopsy to residual disease can occur in patients with early-stage TNBC treated with NAC with pembro. As additional systemic therapy is indicated in patients who do not achieve pCR, accurate tumor marker status is critical. This study highlights the potential impact of reassessment of HR and HER2 status on the surgical tumor specimen. Clinical trials that tailor adjuvant therapy recommendations based on residual biomarker analyses may further improve outcomes for women with high risk TNBC. Table. Discordance in HER2 Status Between Primary Tumor and Residual Specimen Citation Format: Alexis LeVee, Megan Wong, Sarah Flores, Nora Ruel, Heather McArthur, James Waisman, Joanne Mortimer. Receptor discordance after neoadjuvant chemotherapy with pembrolizumab in early-stage triple-negative 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 PO3-03-11.

Abstract ED05-01: Demystifying the Axilla: Challenging scenarios in the upfront surgery setting and after NAC

Abstract Management of the axilla has evolved significantly over time, with a trend toward less extensive axillary surgery. While historically, all patients underwent axillary lymph node dissection (ALND) due to the Halstedian belief that ALND was essential for the cure of breast cancer, advances in systemic therapy, radiotherapy, and understanding of tumor biology have resulted in the abandonment of ALND for a large proportion of patients having upfront surgery with limited nodal disease, and in those with no residual nodal disease after neoadjuvant systemic therapy. Over time, axillary management has become increasingly complicated, with significant variability in real-world management for different clinical scenarios. In this talk, we will address challenging scenarios in axillary management, both in the upfront surgery setting and after neoadjuvant chemotherapy (NAC). In the upfront surgery setting, we will address management of a positive sentinel node in patients treated with mastectomy, management of ≥ 3 positive sentinel nodes after lumpectomy or mastectomy, and the use of sentinel lymph node biopsy for patients with clinically node-positive hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative breast cancer. In the setting of patients receiving NAC, we will discuss the optimal approach to the axilla in patients with residual disease after NAC, and in those with locally advanced breast cancer. As we move away from ALND in low-risk scenarios where data from randomized and prospective trials have demonstrated oncologic safety, we await results from ongoing clinical trials to provide us with high-level evidence regarding the safety of omission of ALND in high-risk patients with more extensive nodal disease. Citation Format: A. Barrio. Demystifying the Axilla: Challenging scenarios in the upfront surgery setting and after NAC [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 ED05-01.

Abstract PO3-27-01: Prediction of pathological complete response to neoadjuvant treatment in loco-regional advancedbreast cancer by using advanced PET/CT metabolic parameters

Abstract Prediction of pathological complete response to neoadjuvant treatment in loco-regional advanced breast cancer by using advanced PET/CT metabolic parameters. Abstract: Background: The standard treatment for locally advanced breast cancer (LABC) is neoadjuvant systemic therapy followed by surgery. The usefulness of FDG PET/CT for evaluating the treatment efficacy in breast cancer is well established; however, the role of quantitative functional PET/CT parameters, such as the metabolic tumor volume (MTV) and total lesion glycolysis (TLG), remains inconclusive. The aim of this study was to determine the correlation between quantitative functional parameters derived from PET/CT in LABC patients at staging and the response to neoadjuvant therapy. Methods: Seventy-eight consecutive patients (aged 25-82 y) with confirmed LABC (stages II-III) who underwent PET/CT as a part of their staging assessment and received neoadjuvant therapy followed by surgery were retrospectively included in this study. All patients underwent an FDG PET/CT at staging; and values of SUV max, SUV mean, MTV, and TLG were determined from the PET/CT studies. The patients were divided into two groups, based on the completeness of histopathologic response to neoadjuvant therapy, both in the primary tumor and axillary lymph nodes. Clinical, imaging and demographic data were collected from patient’s medical record. Results: A complete pathologic response (pCR) was achieved in 33/78 (42%) patients. Among patients with ER/PR positive, Her2-neu negative tumors, in 23/27 (85%) patients only partial pathologic response was reached; 91% of patients with ER/PR negative, Her2-neu positive and 43% of Triple-negative patients had complete pathological? response. For the primary breast tumor response, a higher SUV max, 10.7±5.34 for pCR vs. 7.24±4.62 for non-pCR group was measured, p-value=0.003; threshold value of 6.625. A higher SUV mean in the primary tumor resulted in a significantly higher rate of pCR, 5.95±2.36 vs 4,4±2.16, p=0.004, with a threshold value of 5.795. Neither MTV, not TLG were predictive parameters of the primary tumor response. For lymph nodes response, SUV max and SUV mean had no role in the prediction of pCR. Statistically significant difference however, was found between pCR and non-pCR in MTV values in the involved lymph nodes, with a median =2.13 cm³ [0-7.85] in pCR group vs 5.43 cm³ [3.11-15.3] in non-pCR, p=0.01 (threshold value 2.375) as well as in TLG measurements, with a median of 4.64 [0-19.8] vs. 12.7 [3.21-23.1], p=0.047, (25-75 IQR). Conclusion: Primary breast tumor SUV max/mean values have a significant correlation with the treatment response and threshold values were found. Low MTV and TLG measurements in lymph nodes may predict pCR. Neither MTV nor TLG had were found to have a significant role in the prediction of the primary tumor response. Citation Format: Maisun Shamya, Olga Kagna, Zohar Keidar, Tala Palchan-Hazan, Salem Billan, Roxolyana Abdah-Bortnyak. Prediction of pathological complete response to neoadjuvant treatment in loco-regional advancedbreast cancer by using advanced PET/CT metabolic parameters [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 PO3-27-01.

Abstract PO1-02-09: Efficacy of breast conserving treatment of minimal residual tumors after neoadjuvant therapy for breast cancer

Abstract Background. Determining the most effective drug therapy regimens is one of the top priorities in the individualization of the treatment of patients with breast cancer (BC). Achievement of pathological complete response (pCR) is important prognostic factor, and used as the surrogate primary end point in many clinical trials. According to the literature, the achievement of pCR after neoadjuvant systemic treatment (NST) in breast cancer varies from 30 to 70%. Patients who do not achieve pCR require post-neoadjuvant treatment, even when reaching minimal size of residual tumors. Initially, primary minimal tumors are characterized by high survival rates, which are proved by international and domestic studies. It is required to clarify the survival rates in the presence of a minimal residual tumor (ypT < 10mm) after neoadjuvant systemic therapy and to compare with primary minimal forms of breast cancer (pT1a-b N0M0), characterized by the most favorable prognosis. Objective. Improvement of the effectiveness of treatment of residual minimal forms (ypT1a-b) of BC after NST. Determination of the correlation between the schemes of NST and the rates of tumor response based on the results of postoperative pathological reports including RCB scale. Methods. The study included 602 patients aged 18–65 years with early and locally advanced I–IIIC stage T1-3N1-3M0 breast cancer,who underwent complex or combined treatment. This study included patients treated at the N.N. Petrov National Medical Research Center of Oncology from 2015 to 2021 Conclusion. After reaching a complete pathomorphological response of the tumor to NST (RCB 0), the 5-year disease-free (DFS) and overall (OS) survival rates (DFS – 78.5%; OS 90.4%) were inferior to the survival rates of patients with primary minimal breast cancer (pT1ab N0M0) [DFS – 86.4%; OS – 98.6%]. Neoadjuvant chemotherapy regimens that allow achieving a pathological complete response in triple-negative and HER2- positive breast cancer have been defined. An assessment of adverse factors that affect the effectiveness of breast conserving treatment and correlate with a deterioration in overall survival was performed. Results. Our data analysis revealed that the survival rates (DFS and OS) of patients with minimal residual tumor after neojuvant systemic therapy were not comparable with those in the group of patients with primary minimal breast cancer. Data analysis revealed the most effective combinations of drugs expressed in the rates of pathomorphological response according to the RCB scale. An assessment of adverse factors that affect the effectiveness of organ-preserving treatment and correlate with a deterioration in overall survival was performed. Citation Format: Roman Pesotsky, Vladimir Semiglazov, Petr Krivorotko, Tengiz Tabagua, Konstantin Zernov, Alexander Emelyanov, Viktoria Mortada, Nikolay Amirov, Daria Ulrikh, Valerii Levchenko, Yana Bondarchuk, Diana Enaldieva, Nestan Bekkeldieva, Konsantin Zirov, Sergey Yerechshenko, Vladislav Evseev, Kirill Rychagov, Sergey Novikov, Maria Kazantseva, Larisa Gigolaeva, Elena Zhiltsova, Denis Nesterov, Olga Ivanova, Tatiana Semiglazova. Efficacy of breast conserving treatment of minimal residual tumors after neoadjuvant therapy for 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 PO1-02-09.

Abstract PO5-17-04: Tolerability of pertuzumab in older adults with HER2 positive breast cancer: A single institution experience

Abstract Background: Tumor HER2 over-expression occurs in 10 to 15% of older adults with breast cancer (BC). Combination HER2-directed therapy (pertuzumab and trastuzumab) with chemotherapy (CT) is the standard treatment for early and advanced HER2-positive bc. However, a study of more than 1,300 Medicare beneficiaries showed that about half of patients (pts) aged 65 or older with stage I to III HER2 positive bc did not receive trastuzumab-based therapy. This is likely due to concern for tolerability as older women remain underrepresented in clinical trials of breast cancer making it difficult to extrapolate tolerability of these agents in these patients. In the Neosphere and TRYPHAENA studies, the mean age of pts were 49.8 and 50.6 years, respectively. We examined the real-world tolerability of pertuzumab in combination with trastuzumab and systemic ct in women over the age of 65 with HER2 positive bc. Methods: An IRB approved retrospective review of medical records was conducted evaluating pts over the age of 65 with early or advanced HER2 positive bc treated at The Ohio State University Comprehensive Cancer center from January 1, 2015 to May,1 2020. Descriptive statistics (means, standard deviations, medians and ranges for continuous variables and frequencies and percents for categorical variables) were used to summarize disease and patient characteristics for pts enrolled in this study and treated with pertuzumab. The total number of planned and completed cycles of treatment as well as the number of treatment delays and dose reductions were also summarized using frequencies and percentages. The same descriptive statistics were used to summarize the number of grade II or IV toxicities and pathologic complete response (pCR) in the neoadjuvant setting. Results: A total of 71 pts met inclusion criteria. Mean age was 76 years (SD 4.1). Of these pts, 62 had stage I-III disease and 9 had metastatic disease. Additionally, 68% (48/71) had estrogen positive (ER) disease whereas 32% (23/71) had ER negative disease. Neoadjuvant systemic therapy was provided to 81% (50/62) of non-metastatic pts and 19% (12/62) received adjuvant therapy. The median number of completed neoadjuvant cycles (ct plus trastuzumab and pertuzumab) was 5.4 (SD 1.5). Among those who received pertuzumab with systemic ct in the neoadjuvant setting, 46% (23/50) of pts achieved a pCR (56% for ER negative disease and 41% for ER positive disease) The median number of completed adjuvant cycles (ct plus trastuzumab and pertuzumab) was 4.9 (SD 2.0). Pts with stage I to III disease completed a mean of 8.6 (SD 5.0) targeted therapy cycles (pertuzumab/trastuzumab). Pts with metastatic disease had a median of 5.7 (SD 1.0) cycles of ct plus trastuzumab and pertuzumab and received a mean of 34.4 (SD 36.0) cycles of maintenance pertuzumab. Treatment delay by 7 or more days occurred in 11% (8/71) of pts whereas 25% (18/71) of pts discontinued pertuzumab early. Pertuzumab termination occurred due to toxicity in 44% (8/18), metastasis in 11% (2/18), and other causes in 44% (8/18) of cases. For toxicities, 2% (1/51) of patients reported grade 3 pain, 25% (2/8) reported grade 3 fatigue, and 12% reported grade 4 diarrhea (1/8) (Table 1). Conclusions: Our study showed that pertuzumab was well tolerated in older pts with bc in the real-world setting. However, 25 % of pts still discontinued pertuzumab early which illustrates the importance of identifying pts who are at higher risk for toxicities prior to starting treatment. Table 1 Reported adverse events in patients age 65 and older receiving pertuzumab Citation Format: Nicole Williams, Austin Warmbier, Dureti Doto, Marilly Palettas, Julie Stephens, Dionisia Quiroga, Kai Johnson, Ashley Pariser, Mathew Cherian, Sagar Sardesai, Daniel Stover, Margaret Gatti-Mays, Robert Wesolowski, Bhuvana Ramaswamy. Tolerability of pertuzumab in older adults with HER2 positive breast cancer: A single institution experience [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 PO5-17-04.

Abstract PO3-08-09: Unique molecular signatures of germline mutations in low expression of human epidermal growth factor receptor 2 (HER2) breast cancer

Abstract Background: Overexpression of human epidermal growth factor receptor 2 (HER2) in breast cancer (BC) is associated with lower survival and higher risk of disease recurrence. A new subtype of HER2-low BC which has been proposed from several studies demonstrates that HER2-low patients have distinct somatically genetic alterations and clinical outcomes. We have previously reported that HER2-low BC had distinct clinical and somatic mutational feature compared with HER2-zero and HER2-high tumors. We have therefore extended studies by comparing germline mutation expression among these HER2 subgroups. Methods: 530 Chinese women with BC were enrolled in a prospective protocol between May 2021 to March 2023 at Guangdong Provincial People's Hospital. Genomics data was generated from a gene panel that surveys 102 tumor mutations. Germline variants were classified into pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB) and benign (B) groups according to the ACMG/AMP Standards and Guidelines. The cohort was divided into three groups based on HER2 status as HER2-zero (n = 107), HER2-low (n = 259), and HER2-high (n = 127) according to immunohistochemistry and/or fluorescence in situ hybridization results. Results: The most common mutated genes were ATM, FANCD2, ATR, BRACA2, RECQL4 and APC. A total of 71 pathogenic or likely pathogenic (P/LP) mutations were identified in 25 cancer susceptibility genes from 64 patients (12.16%). The most frequent mutated P/LP genes are BRCA2, BRCA1, PALB2, PMS2, MUTYH and PTEN in the HER2-low group; BRCA2, BRCA1 and PALB2 in the HER2-zero cohort; Interestingly, among the nine HER2-high patients, we detected unique P/LP genes in each sample including MRE11, FANCM, ATM, FLCN, NTRK1, TP53, BRCA1, CHEKE2 and FANCA. In addition to P/LP mutations, 751 variants of uncertain significance (VUS) in 95 cancer susceptibility genes were also detected in 361 patients (68.11%). The most frequent mutated VUS mutations occurred genes are FANCD2, ATM, RECQL4, RAD54B and ATR in HER2-low group; ATM, FANCA, POLE, MSH2 and FANCD2 in HER2-zero cohort; and ATM, BRCA2, RECQL4, POLE, FANCI and FANCM for HER2-high patients. Most of mutated genes were homologous recombination repair (HRR) or DNA damage repair (DDR) pathway related genes. Several genes were differentially altered across HER2 subgroups, including the mutation frequency of the BMPR1A (p=0.0344), MSH2 (p=0.0103), and RAD51C (p=0.0336) genes that were significantly higher in HER2-zero group. It’s worth noting that RAD51C was only mutated in HER2-zero subgroup. BMPR1A and MSH2 were also mutated in HER2-low patients. Differentially mutated genes in specific HER2 subgroups may contribute to better research and choice of future therapeutic approaches. In 115 patients who received neoadjuvant therapy and 84 of them were evaluable for pathological response data, HER2-low patients had lower pathological complete response (pCR) rates than HER2-zero and HER2-high subgroups (p=0.0008). In particular, DDR pathway gene ERCC1 have significantly higher mutation frequency in pCR patients (p=0.0115). Conclusion: HER2-low BC patients have distinct germline mutational signatures and differential clinical outcomes under neoadjuvant systemic therapy. These results have provided additional evidence that HER2-low patients comprise a fourth subtype of BC that needs to be accounted for separately in terms of clinical treatment and outcome reporting. Keywords: breast cancer, germline mutations, human epidermal growth factor receptor 2 (HER2), HER2-low, targeted therapy, next-generation sequencing Table 1. List of most frequent mutated genes in HER2-zero, HER2-low and HER2-high groups Citation Format: Ning Liao, Weiqi Zhang, Liangqiu Liu, Wendy Wu, Siqi Wang, Li Cao, Jianguo Lai, Xueying Zhang, Airong Yang, Yulei Wang, Cheukfai Li, Guochun Zhang, Chongyang Ren, Lingzhu Wen. Unique molecular signatures of germline mutations in low expression of human epidermal growth factor receptor 2 (HER2) 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 PO3-08-09.

Abstract PO2-13-07: SMARCA2 compensation of SMARCA4 loss mediates adaptive resistance to neoadjuvant systemic therapy in triple-negative breast cancer: paired transcriptomic analysis of pre- and post-treatment samples from NeoSTOP and NeoPACT

Abstract Objectives/Rationale: Triple-negative breast cancer (TNBC) patients with residual disease (RD) after neoadjuvant systemic therapy (NAST) are at high risk for disease recurrence and death. While multiple prognostic biomarkers associated with response to NAST have been identified, adaptive resistance mechanisms to NAST remain poorly understood. Identifying and characterizing adaptive resistance mechanisms can illuminate novel therapeutic approaches and improve outcomes for TNBC patients with RD. Methods: Total RNA was isolated from pre-treatment and paired surgical specimens (for patients with RD) from TNBC patients treated with chemotherapy on the NeoSTOP (NCT02413320) or chemoimmunotherapy on the NeoPACT (NCT03639948) neoadjuvant trials and was subjected to RNA exome sequencing. Comparative marker selection analysis was performed by computing the two-sided paired samples t-test for each gene followed by pre-ranked gene set enrichment analysis (GSEA) amongst 23,797 annotated gene sets. Gene sets with false-discovery rate (FDR) corrected P values < 0.001 were determined to be significant. Results: Pre-treatment sequencing data were available for N=200 patients and the overall pathologic complete response (pCR) rate was 56.5%. Paired pre- and post-treatment sequencing data were available for N=58 patients with RD (N=27 from NeoSTOP and N=31 from NeoPACT). 165/23,797 gene sets were significantly enriched in post-treatment compared to pre-treatment samples. SHEN_SMARCA2_TARGETS_UP (M29) was among the top five significantly enriched gene set and was selected for further analysis based on the known role of the SWI/SNF complex in cell survival and the availability of clinically viable SMARCA2 degraders. Pre-treatment SMARCA4 expression was associated with pCR, with lower median expression noted in patients with RD compared to patients who achieved pCR (P=0.04). Pre-treatment SMARCA2 expression was not associated with pCR (P=0.48). On paired sample analysis there was pronounced downregulation of SMARCA4 in post-treatment compared to pre-treatment samples in all patients (mean Z=-1.46, P< 0.0001), in patients treated with chemotherapy (mean Z=-1.65, P< 0.0001), and in patients treated with chemoimmunotherapy (mean Z=-1.28, P< 0.0001). Although there was no difference in SMARCA2 expression between paired pre- and post-treatment samples (mean Z=0.03, P=0.83), there was enrichment of SMARCA2 target expression on GSEA analysis (NES=2.63, FDR q< 0.00001) indicating that SMARCA2 activity is compensating for therapy-induced SMARCA4 loss. Conclusions: We identified 165 gene sets that were significantly enriched in paired post-treatment compared to pre-treatment TNBC samples. Altered activity of the SMARCA2 subunit of the SWI/SNF chromatin remodeling complex was identified as one of the top hits. SMARCA2 and SMARCA4 are mutually exclusive subunits of SWI/SNF, and inactivation of both SMARCA2 and SMARCA4 is synthetic lethal. We observed an association of lower pre-treatment SMARCA4 expression with resistance to NAST and pronounced therapy-induced downregulation of SMARCA4 and induction of SMARCA2 target genes in post-treatment compared to pre-treatment samples, suggesting that SMARCA2 compensates for adaptive SMARCA4 loss. SMARCA2 degraders are in early-phase clinical trials and are known to induce synthetic lethality in SMARCA4-deficient cells. Our results identify adaptive loss of SMARCA4 and synthetic lethal targeting of compensatory SMARCA2 as an attractive therapeutic target in TNBC patients with RD after neoadjuvant chemotherapy or chemoimmunotherapy. Citation Format: Shane Stecklein, Rachel Yoder, Joshua Staley, Zachary Schmitt, Anne O'Dea, Lauren Nye, Deepti Satelli, Gregory Crane, Rashna Madan, Maura O'Neil, Andrew Godwin, Harsh Pathak, Qamar Khan, Joyce O'Shaughnessy, Priyanka Sharma. SMARCA2 compensation of SMARCA4 loss mediates adaptive resistance to neoadjuvant systemic therapy in triple-negative breast cancer: paired transcriptomic analysis of pre- and post-treatment samples from NeoSTOP and NeoPACT [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 PO2-13-07.

Abstract PO2-10-06: The Rising Burden of Contraception Requirements in Breast Cancer Clinical Trials: Time for Change?

Abstract Background: Breast cancer clinical trials often involve therapies with potentially deleterious effects on the fetus and the baby in the event of pregnancy or breastfeeding. Consequently, eligibility criteria include contraceptive requirements for both the patient and their partner. Patient feedback on the burden of requirements in clinical trials prompted an evaluation of changes in contraceptive requirements in breast cancer clinical trials over the past two decades. Methods: Breast cancer ClinicalTrials.gov trials protocols over three periods of enrollment were reviewed: 01/01/2001 - 01/01/2002, 01/01/2011 - 01/01/2012, and 01/01/2021 - 01/01/2022. Inclusion criteria: 1. Interventional studies including (neo)adjuvant or palliative systemic therapy, 2. Premenopausal female patients. Data, including the required number, types, and duration of contraceptive strategies, treatment regimen, and study design, were collated. A descriptive analysis by time period was performed. Results: 305 studies were included from the three periods: 63 (2001), 127 (2011), and 115 (2021). Of these, contraception requirements were specified in ClinicalTrial.gov protocol information in 4, 61, and 71 CT for 2001, 2011, and 2021, respectively, limiting our analyses in the two later periods. Complete data is available in Table 1. Conclusions: Our data demonstrates a time trend towards more stringent contraception requirements in breast cancer clinical trials inclusion criteria. The impact of contraception burden on enrollment, patient compliance, and investigator insight warrants further assessment. Citation Format: Camila Chiodi, Munzir Hamid, Catherine Weadick, Maeve Hennessy, Ana Martin-Quesada, Louise Kenny, Matteo Lambertini, Ines Vaz Luis, Seamus O'Reilly. The Rising Burden of Contraception Requirements in Breast Cancer Clinical Trials: Time for Change? [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 PO2-10-06.

Abstract PO4-19-12: Trial in progress: An Observational Study to Examine Changes in Metabolic Syndrome Components in Patients With Breast Cancer Receiving (Neo)Adjuvant Aromatase Inhibitors

Abstract Background: (Neo) adjuvant systemic therapy has been shown to adversely impact metabolic health manifested as weight gain, dyslipidemia, and insulin resistance, which ultimately lead to the development of metabolic syndrome (MetS). MetS increases the risk of development for type 2 diabetes mellitus and cardiovascular disease and is associated with an increased risk of breast cancer recurrence, death due to breast cancer, and all-cause mortality. We have previously reported that 76% of metabolically healthy women receiving (neo) adjuvant chemotherapy will develop MetS at a median of 15 weeks. The impact of aromatase inhibitors (AIs) on metabolic health has not been systematically assessed in a longitudinal study. We hypothesize that AIs in the (neo) adjuvant setting will alter metabolic parameters and have embarked on a clinical trial to study this. Methods: This is a prospective observational study that will include: postmenopausal patients with newly diagnosed, early-stage hormone receptor (HR)-positive breast cancer with planned (neo)adjuvant treatment with an AI. Participants will be excluded if they have received or have planned treatment with (neo)adjuvant chemotherapy or are currently receiving antidiabetic medications or cholesterol-lowering agents. All patients will undergo a baseline assessment that includes: BMI, physical exam inclusive of blood pressure, waist circumference, assessment of body fat, lipid profile, insulin, metabolic biomarkers, and completion of the Functional Assessment of Cancer Therapy – Endocrine Symptoms (FACT-ES). Following institution of an AI, reassessment of the aforementioned tests will be repeated after 4 months and 12 months of therapy. The primary endpoint is the change in insulin resistance (as measured by HOMA-IR, homeostatic model assessment for insulin resistance) at 4 months. Secondary endpoints include the change in HOMA-IR at 12 months and the change in individual MetS components, metabolic biomarkers, anthropometric measurements, as well as FACT-ES scores from baseline to 4- and 12-months of AI treatment. The mean paired differences will be calculated for HOMA-IR measurements as well as for the secondary endpoints, and the 1-sided paired t-test will be used to test for statistical significance. One-way analysis of covariance will be used to compare means while adjusting for age, race/ethnicity, and BMI. Using a 1-sided paired t-test for the mean difference in HOMA-IR measurements from baseline to 4 months, we will have 80% power to detect an effect size of 0.405 with 40 patients (α = 0.05). Enrollment began in April 2023 and is ongoing. Contact alevee@coh.org for more information. Given the increased recognition of the importance of metabolic health in breast cancer outcomes, this data will inform future trials that focus on maintaining metabolic health in breast cancer survivors. Citation Format: Alexis LeVee, Nora Ruel, Victoria Seewaldt, Joanne Mortimer. Trial in progress: An Observational Study to Examine Changes in Metabolic Syndrome Components in Patients With Breast Cancer Receiving (Neo)Adjuvant Aromatase Inhibitors [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 PO4-19-12.

Abstract PO5-19-01: The HER2-RADiCAL study (Response ADaptive CAre pLan) – Tailoring treatment for HER2 positive early breast cancer

Abstract Background The presence or absence of residual disease following neoadjuvant systemic anti-cancer therapy (neoSACT) for HER2-positive early breast cancer (HER2+ EBC) provides powerful prognostic information. Pathological complete response (pCR) following neoSACT, particularly in patients with earlier clinical TNM stage at diagnosis, identifies a population with excellent survival outcomes in whom the balance of toxicity associated with the current treatment pathway may be disproportionate to absolute clinical benefit. Aims >HER2-RADiCAL seeks to reduce the treatment burden and healthcare costs of treating HER2+ EBC by testing the hypothesis that pCR can be used as a functional response biomarker to select patients who can safely receive less systemic therapy with minimal/no loss of efficacy. Trial design and eligibility criteria HER2-RADiCAL is a response-directed interventional cohort/threshold-crossing design study embedded within a real-world data-driven clinical pathway model. Patients with ER-positive or negative HER2+ EBC with cT1N1 or cT2N0-1 stage at diagnosis are eligible after completion of standard of care neoSACT and locally determined pCR (ypT0/Tis ypN0). Patients with pathological features consistent with previous malignant involvement in >4 nodes are not eligible. Adjuvant trastuzumab +/- pertuzumab may have continued prior to study entry provided no more than 9 cycles of trastuzumab are received. After registration all participants receive a total of 9 cycles of trastuzumab including those administered prior to study entry. Participants receive no further pertuzumab and no adjuvant chemotherapy. Adjuvant endocrine therapy and radiotherapy are given as per standard of care. Central pathology review of pCR status will be conducted in a subset of cases. A Study Within a Trial (SWAT) will explore identification of factors influencing patient decision-making for participation in studies of response-adapted treatment. Statistical methods The primary endpoint is relapse-free interval. Recruitment of 720 participants over 3.5 years will provide 90% power to exclude an event rate >6.5% at 3 years (expected event rate ≤4%). Secondary endpoints include relapse-free survival, invasive breast cancer-free survival, invasive disease-free survival, distant recurrence-free interval, breast cancer-free interval, overall survival, treatment pathway adherence and cost-effectiveness. An interventional cohort is preferred to a randomised non-inferiority trial based on the known event rate in this population which is sufficiently low such that any deviation from this expected event rate would indicate failure of the reduced therapy strategy. Real-world data driven clinical pathway model Health economic modelling will compare the protocol-driven study cohort with two comparator pathways: a non-response adapted maximum therapy pathway (the standard clinical pathway prior to the study) and a real-world representative pathway derived from anonymised data for all patients treated for HER2+ EBC within the UK NHS. Patient and public involvement Our PPI partners continue to shape this research, holding key roles as trial management group members, overseeing progress of the study, contributing to protocol amendment development, and design and implementation of the SWAT. Current status The first patient was enrolled in December 2021. At 10th July 2023, 25 research sites have opened with 39 participants recruited. Site opening continues with a minimum target of 40. Responding to continued use of anthracycline-based regimens in UK practice, eligibility criteria have recently been extended to permit entry of patients who have received anthracycline-containing neoSACT. For further information contact her2radical-icrctsu@icr.ac.uk. Citation Format: Iain Macpherson, Stuart McIntosh, Lucy Kilburn, Holly Tovey, Laura Moretti, Katie Goddard, Indrani Bhattacharya, Clinton Boyd, Cliona Kirwan, Ciara O'Brien, Duncan Wheatley, Jennifer Glendenning, Mairead MacKenzie, Hilary Stobart, Claire Snowdon, Andrew Wardley, Abeer Shaaban, Peter Hall, David Cameron, Judith Bliss. The HER2-RADiCAL study (Response ADaptive CAre pLan) – Tailoring treatment for HER2 positive 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 PO5-19-01.

Abstract PO5-21-07: Mitomycin: its developmental role in the treatment of patients with BRCA - associated triple-negative early and locally advanced breast cancer

Abstract Rationale. BRCA-associated triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer with high sensitivity to chemotherapy, which leads to increased interest in the development of new strategies for neoadjuvant treatment of patients with a triple-negative tumor phenotype. The aim of the study is to determine the role of adding platinum to standard neoadjuvant systemic therapy in patients with primary BRCA-associated TNBC, to evaluate the effect of platinum preparations on relapse-free survival in patients of this category, to determine the role of adding mitomycin to platinum in patients with primary BRCA-associated TNBC. Materials and methods. The study included 80 patients diagnosed with primary BRCA - associated TNBC, divided into 3 groups according to the treatment. Each group was subdivided depending on the final pathomorphological result and the presence of relapses. Results. 80 patients with primary BRCA-associated TNBC were divided into 3 groups depending on the ongoing neoadjuvant chemotherapy (NACT). Group I included 48 (60%) patients who received the AC-T regimen, in group II — NAC according to the AC-TCarb regimen, 27 (33.75%) patients, in group III — NAC with mitomycin in combination with cisplatin, 5 (6.25%) of patients. A comparative analysis of the results of the frequency of achieving complete pathomorphological regression (pCR), depending on the addition of a platinum drug to standard NAC, showed the advantage of group II compared to group I (73.7% vs. 41.2%, respectively, p = 0.0433). Taking into account the ongoing NAC regimens, with a median follow-up of 20.7 months, patients of group I had a slightly higher risk of relapse compared to patients of group II (p = 0.099). Patients of group III demonstrated the achievement of pCR in 66.6% of cases (2/3) during the full course of NAC, 2 patients of group III did not complete the planned course of NAC for medical reasons, due to the development of a pronounced nephrotoxic effect. During the observation period of group III, no cases of relapse were recorded. Conclusions.The addition of platinum drugs to the standard anthracycline/taxane NAPCT regimen in patients with primary BRCA-associated TNBC, results in a higher pCR rate, which entails a reduced risk of disease recurrence.The use of the new NAC regimen with mitomycin in combination with platinum compounds has promising results in patients with this oncopathology, which deserves a more detailed clinical evaluation.Performinga full course of planned NAC has a positive tendency in achieving pCR in patients of this category. Keywords: BRCA1/2 mutation; triple negative breast cancer; platinum preparations; mitomycin; neoadjuvant chemotherapy. Citation Format: Petr Krivorotko, Evgeniy Imyanitov, Diana Enaldieva, Elena Zhiltsova, Roman Donskih, Anna Sokolenko, Laysan Shaikhelislamova, Larisa Gigolaeva, Tengiz Tabagua, Alexander Komyakhov, Kirill Nikolaev, Konstantin Zernov, Sergey Yerechshenko, Roman Pesotsky, Nikolay Amirov, Alexander Emelyanov, Viktoria Mortada, Yana Bondarchuk, Vladislav Semiglazov. Mitomycin: its developmental role in the treatment of patients with BRCA - associated triple-negative early and locally advanced 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 PO5-21-07.

Abstract PO2-03-06: Pathological complete response with chemotherapy and immune checkpoint inhibition in triple negative inflammatory breast cancer (TN-IBC)

Abstract BACKGROUND: Patients with stage III inflammatory breast cancer (IBC) are treated with tri-modality therapy consisting of neoadjuvant systemic therapy followed by modified radical mastectomy and post-mastectomy radiation therapy. Triple negative IBC (TN-IBC) is the subtype of IBC associated with the worst survival outcomes. Pathological complete response (pCR) rates after neoadjuvant chemotherapy have been historically low, with reports ranging between 13% and 42%. It is unknown if the addition of immune checkpoint inhibition to chemotherapy leads to improved pCR rate in TN-IBC as these patients were underrepresented in the seminal studies that led to the approval of chemoimmunotherapy for high-risk early-stage triple negative breast cancer (TNBC). METHODS: We conducted a retrospective analysis of patients with stage III TN-IBC who underwent breast surgery after receiving neoadjuvant chemoimmunotherapy. Patients were seen at Dana-Farber Cancer Institute (DFCI) or MD Anderson Cancer Center (MDACC). The analysis population consisted of all patients that were seen at either institution no more than 30 days after starting immunotherapy. The primary objective was the estimation of the pCR rate. An additional cohort of patients with TN-IBC treated with neoadjuvant chemotherapy and pembrolizumab while participating in the multi-institutional PELICAN trial (NCT03515798) will be added to the analysis at the time of the meeting. RESULTS: Thirty-seven patients (16 DFCI, 21 MDACC) were identified as having stage III TN-IBC and having received neoadjuvant chemoimmunotherapy. Twenty-five patients met criteria for inclusion in the analysis population. Patients in the DFCI cohort initiated treatment with chemoimmunotherapy between May 2021 and June 2022, and in the MDACC cohort between June 2021 and October 2022. Most patients were White (N=20, 80%), premenopausal (N=15, 60%) and overweight/obese (N=19, 76%). All patients received pembrolizumab-based therapy (Table 1). Among the 25 patients in the analysis population, 10 (40%) (95% CI: 21% to 61%) achieved a pCR, 6 patients experienced RCB-II and 9 RCB-III. At the time of last follow up, 84% of patients were alive. The results will be updated at the time of the meeting to include an additional cohort of 17 patients from the PELICAN trial. CONCLUSIONS: The addition of immune checkpoint inhibition to neoadjuvant chemotherapy led to a higher pCR rate in TN-IBC than most historical estimates. However this is still lower than what has been reported in TNBC in general. The investigation of novel systemic therapies is warranted in TN-IBC. Table 1. Patient characteristics and treatment received (analysis population) Citation Format: Filipa Lynce, Samuel Niman, Anthony Gonçalves, Megumi Kai, Sean Ryan, Elizabeth Troll, Rachel Layman, Antonio Giordano, Azadeh Nasrazadani, Faina Nakhlis, Jennifer Bellon, Laura Warren, Caroline Block, Susan Schumer, Anthony Lucci, Savitri Krishnamurthy, Florence Lerebours, Florence Dalenc, Christelle Levy, Thierry Petit, Marianne Leheurteur, Thomas Bachelot, Olivier Trédan, Sylvain Ladoire, Leonor Lopez Almeida, Christophe Zemmour, Sara Tolaney, Vicente Valero, François BERTUCCI, Meredith Regan, Wendy Woodward. Pathological complete response with chemotherapy and immune checkpoint inhibition in triple negative inflammatory breast cancer (TN-IBC) [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 PO2-03-06.

Abstract PO5-26-04: The value of skin involvement in achieving of pCR in patients with locally advanced breast cancer

Abstract Objective: The management of patients with locally advanced breast cancer (LABC) with skin involvement (edema or thickening) continues to be one of the most controversial topics in mammology. The most recommended conventional treatment strategies include systemic therapy (chemotherapy/hormone therapy/biological agents) followed by local therapy (surgery and/or radiation therapy). However, approximately 1/3 of patients with locally advanced breast cancer are “resistant” to neoadjuvant chemotherapy (which is manifested by the persistence of skin involvement/edema/thickening). In this study, we aimed to identify the relationship between skin involvement and clinicopathological features of LABC patients. In particular, we sought to develop the algorithm for skin involvement measurement and examine the impact of skin involvement on the rate of pCR. Materials and methods: We performed a retrospective analysis of 182 patients diagnosed with LABC from 2010 to 2018 at N.N. Blokhin National Cancer Research Center. All patients were treated with neoadjuvant hormone- or chemotherapy and were considered as borderline for surgical resection because of partial skin edema. Ninety one women received surgery with consecutive radiotherapy (first group) and 50 women (second group) received radiotherapy (total dose 50 Gy) with consecutive surgery after systemic treatment. We developed the algorithm for skin involvement measurement, using a series of formulas. We further interrogated the impact of skin involvement on the rate of breast and lymph node pathological response in every group. Results: The median percentage of skin edema before systemic therapy was 76.3% in the first group and 70.1% in the second group. The median percentage of skin edema after systemic therapy was 62.3% in the first group and 69.1% in the second group. There wasn`t a statistically significant difference between the two groups (р=0,675 and р = 0,286, respectively). Breast pCR was seen in 19,7% (n=18) of the first group patients and partial response was seen in 72.6% (n=66). Breast pCR was seen in 30% (n=15) of the second group patients and partial response was seen in 70% (n=35). Results showed no significant differences between groups, р=0,342 and р = 0,12, respectively. Nodal pCR was reported in 23,9% (n=16) and partial response in 50,8% (n=34) of the 67 node-positive patients. Nodal pCR was reported in 31,6% (n=12) and partial response in 65,8% (n=29) of the 38 node-positive patients of the second group. There was no statistical difference in the groups, p >0,05. Conclusion: Increasing attention has been paid to LABC patients due to the clinical commonness and the complexity of treatment. Our study showed that LABC patients with incomplete clinical response to neoadjuvant systemic therapy can achieve pCR or partial response of tumor despite partial skin edema. In this study we developed the algorithm for skin involvement measurement. We hope that knowledge about volume of skin involvement revealed by this study might shed light on individualized therapies for these patients. In future, it allows to evaluate criteria of tumor resectability to improve patient selection. Therefore, prospective randomized trials are needed to improve optimization of the local treatment. Citation Format: Viktory Amosova, Alexander Petrovskiy, Oxana Trofimova, Mona Frolova, Alexey Rumyantsev. The value of skin involvement in achieving of pCR in patients with locally advanced 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 PO5-26-04.

Abstract PO1-19-06: Physical exercise during neoadjuvant chemotherapy for breast cancer as a mean to increase pathological complete response rates: the randomized Neo-ACT trial

Abstract Introduction In early breast cancer, neoadjuvant chemotherapy (NACT) is increasingly used. The proof of efficacy is pathologically complete response (pCR), i.e. the absence of invasive tumour in breast and lymph nodes at surgery. Today, pCR is a common endpoint in pharmaceutical trials since it is significantly associated with survival especially in triple-negative and HER2-positive subtypes. Apart from the mitigation of treatment-related toxicity and symptoms, physical exercise mediates anti-tumoral systemic effects associated with tumour regression in preclinical and clinical models. The aim of Neo-ACT is to test the hypothesis that physical exercise can improve pCR rates in breast cancer patients receiving NACT. Method The Neo-ACT trial is an international prospective clinical trial, randomising T1-3N0-2 breast cancer patients planned for NACT to either a home-based physical exercise intervention supported by a mobile application or routine care. The primary endpoint is pCR; secondary endpoints are patient-reported quality of life, toxicity-related outcomes, and oncological outcomes such as Residual Cancer Burden, objective radiological tumour response, as well as overall, breast cancer-specific and disease-free survival at 2, 5 and 10 years. The intervention consists of a combination of high-intensity interval and resistance training of progressing intensity, and includes two weekly 60-min exercise sessions plus at least 150 min of moderate to vigorous physical activity per week. The Neo-ACT has been registered at clinicaltrials.gov on January 11, 2022 (NCT05184582). Statistical methods Patients will be randomized in a 1:1 fashion. It is anticipated that the rate of the primary endpoint pCR will be approximately 30% in the control arm (all subtypes). We aim to increase the rate of pCR in the experimental arm to 40%, i.e. a 10 percentage points increase, which is regarded clinically relevant since it would translate into improved disease-related outcomes. With a power of 80% and an alpha of 5%, a total of 712 patients have to be included; 356 in each arm. Accounting for a drop-out of 10%, we aim to include 790 patients. Stratification at the moment of computerized randomization is based on site of treatment (hospital) and biological tumour subtype (ER+HER2-, ER+HER2+, ER-HER2+, ER-HER2-). All outcomes will primarily be analysed using an intention-to-treat approach, i.e. all study subjects will belong to the treatment group (exercise intervention or control) they were assigned to, disregarding compliance. As sensitivity analysis, all outcomes will also be analysed using a per-protocol approach, meaning that participants in the intervention group who comply with less than 65% of the prescribed physical exercise program, and participants who complete less than 40% of the planned neoadjuvant systemic therapy (around two 3-weekly courses) will be excluded from analysis. Present accrual The Neo-ACT trial has started enrolment at the first site in December 2022 and since then initiated a further five Swedish and one Finnish site. Until June 15, 2023, 26 participants had been randomized in the trial. A feasibility questionnaire is distributed via the EUBREAST network which officially supports this trial and has added the designation EUBREAST12-R. Further participating sites can be accommodated depending on volume, competing trials and language requirements for the mobile application. Contact: jana.de-boniface@ki.se Citation Format: Jana de Boniface, Cecilia Haddad Ringborg, Renske Altena, Yvonne Wengström. Physical exercise during neoadjuvant chemotherapy for breast cancer as a mean to increase pathological complete response rates: the randomized Neo-ACT 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 PO1-19-06.