Early Triple-negative Breast Cancer Research Articles

Safety and tolerability of olaparib combined with breast radiotherapy in patients with triple-negative breast cancer: Final results of the RADIOPARP phase 1 trial.

534 Background: Preclinical studies have demonstrated that triple-negative breast cancer (TNBC) cells were sensitive to PARP inhibitors when used as radiosensitizers. Combining PARP-inhibitors with radiotherapy may consequently enhance the biological effectiveness of the irradiation, leading to improved locoregional control in TNBC patients. We aimed to establish the appropriate dosing and the safety profile of Olaparib used as a radiosensitizer in combination with radiotherapy in TNBC patients with residual disease after neoadjuvant chemotherapy. Methods: RADIOPARP (NCT03109080) was a prospective phase I dose-escalation trial establishing the tolerance profile of Olaparib combined with breast radiotherapy in high-risk early TNBC patients. Inclusion criteria were resected TNBC with non-complete pathological response after neoadjuvant chemotherapy, or unresectable TNBC despite prior neoadjuvant chemotherapy. Olaparib was started seven days before irradiation and continued during radiotherapy. A time-to-event continual reassessment method was used to increase Olaparib through four increasing dose levels (50mg, 100mg, 150mg or 200mg twice a day) with a 25% maximum probability rate of dose-limiting toxicities (DLT). Radiotherapy delivered 50 Gy to the breast or to the chest wall, with or without lymph node irradiation. Toxicities were graded according to CTCAE (version 4.03). Homologous recombination (HR) proficiency status was genetically determined based on shallow whole genome sequencing. Results: Twenty-four TNBC patients were enrolled between 09/2017 and 11/2019. Olaparib was escalated to 200 mg twice a day without DLT and the MTD was not reached. With a median follow-up of 34 months, no late treatment-related grade ≥ 3 toxicity was observed, and the maximum observed toxicities were limited to grade 2 breast pain (n=2), fibrosis (n=2), deformity (n=1) and telangiectasia (n=1). Three-year OS and EFS were 83% [95% CI: 70%-100%] and 65% [51%-91%], respectively. HR proficiency status was not associated with OS and EFS. Conclusions: Olaparib used as a radiosensitizer in combination with radiotherapy in TNBC patients was well-tolerated. The MTD was not reached, and no significant late toxicity was reported. For future trials evaluating the anti-tumor efficacy of this combination, an Olaparib dose of 200 mg twice a day should be considered. Clinical trial information: NCT03109080.

New Achievements for the Treatment of Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC) constitutes a heterogeneous group of malignancies that are often aggressive and associated with a poor prognosis. The development of new TNBC treatment strategies has become an urgent clinical need. Diagnosis and subtyping of TNBC are essential to establish alternative treatments and targeted therapies for every TNBC patient. Chemotherapy, particularly with anthracycline and taxanes, remains the backbone for medical management for both early and metastatic TNBC. More recently, immune checkpoint inhibitors and targeted therapy have revolutionized cancer treatment. Included in the different strategies studied for TNBC treatment is drug repurposing. Despite the numerous medications available, numerous studies in medicinal chemistry are still aimed at the synthesis of new compounds in order to find new antiproliferative agents capable of treating TNBC. Additionally, some supplemental micronutrients, nutraceuticals and functional foods can potentially reduce the risk of developing cancer or can retard the rate of growth and metastases of established malignant diseases. Finally, nanotechnology in medicine, termed nanomedicines, introduces nanoparticles of variable chemistry and architecture for cancer treatment. This review highlights the most recent studies in search of new therapies for the treatment of TNBC, along with nutraceuticals and repositioning of drugs.

Tumor-Infiltrating Lymphocytes (TILs) in Early Breast Cancer Patients: High CD3+, CD8+, and Immunoscore Are Associated with a Pathological Complete Response.

Simple SummaryIn 2021, the World Health Organization announced that breast cancer had overtaken lung cancer to become the most common cancer globally, accounting for 12% of all new cancer cases, with younger women resident in low-income countries having the lowest 5-year survival rates. The main aim of the current study was to evaluate the prognostic utility of an innovative, objective, computer-assisted, digital imaging procedure known as the Immunoscore for clinical research (ISCR) as a strategy to reveal the efficiency of the anti-tumor cellular immune landscape of the tumor microenvironment (TME) in biopsies taken from women diagnosed with early breast cancer prior to administration of neoadjuvant chemotherapy followed by surgical resection. Our results demonstrated the ability of the ISCR to enumerate tumor-infiltrating lymphocytes in the TME and, in particular, to illustrate the spatial arrangement of these cells, which, importantly, correlated with clinical outcome, measured as the pathological complete response.Background: Tumor-infiltrating lymphocytes are associated with a better prognosis in early triple-negative breast cancer (TNBC). These cells can be enumerated in situ by the “Immunoscore Clinical Research” (ISCR). The original Immunoscore® is a prognostic tool that categorizes the densities of CD3+ and CD8+ cells in both the invasive margin (IM) and center of the tumor (CT) in localized colon cancer, yielding a five-tiered classification (0–4). We evaluated the prognostic potential of ISCR and pathological complete response (pCR) following neoadjuvant chemotherapy (NACT). Methods: The cohort included 53 TNBC, 32 luminal BC, and 18 HER2-positive BC patients undergoing NACT. Pre-treatment tumor biopsies were immune-stained for CD3+ and CD8+ T-cell markers. Quantitative analysis of these cells in different tumor locations was performed using computer-assisted image analysis. Results: The pCR rate was 44%. Univariate analysis showed that primary tumor size, estrogen-receptor negative, progesterone-receptor negative, luminal vs. HER2-positive vs. TNBC, high Ki-67, high densities (cells/mm2) of CD3 CT, CD8+ CT, CD3+ IM, and CD8+ IM cells were associated with a high pCR. ISCR was associated with pCR following NACT. A multivariate model consisting of ISCR and the significant variables from the univariate analysis showed a significant trend for ISCR; however, the low sample size did not provide enough power for the model to be included in this study. Conclusions: These results revealed a significant prognostic role for the spatial distributions of the CD3+, and CD8+ lymphocytes, as well as the ISCR in relation to pCR following NACT.

Impact of HER2 Status on Pathological Response after Neoadjuvant Chemotherapy in Early Triple-Negative Breast Cancer.

Simple SummaryHER2-low (IHC 1+ or IHC 2+/ISH-) breast cancer (BC) is an emerging subtype of BC with promising results with antibody drug conjugate (ADC) in the metastatic setting. In the early setting, few data have been reported regarding the predictive and prognostic impact of HER2-low status in triple-negative BC (TNBC).Purpose: Investigates the link between HER2 status and histological response after neoadjuvant chemotherapy in patients with early TNBC. Methods: We retrieved clinical and anatomopathological data retrospectively from 449 patients treated for the first time with standard neoadjuvant chemotherapy for early unilateral BC between 2005 and 2020. The primary endpoint was pathological complete response (pCR, i.e., ypT0 ypN0), according to HER2 status. Secondary endpoints included invasive disease-free survival (I-DFS) and overall survival (OS). Results: 437 patients were included, and 121 (27.7%) patients had HER2-low tumours. The pCR rate was not significantly different between the HER2-low group vs. the HER2-0 group (35.7% versus 41.8%, p = 0.284) in either univariate analysis or multivariate analysis adjusted for TNM classification and grade (odds ratio [OR] = 0.70, confidence interval [CI] 95% 0.45–1.08). With a median follow-up of 72.9 months, no significant survival differences were observed between patients with HER2-low tumours vs. patients with HER2-0 tumours in terms of I-DFS (p = 0.487) and OS (p = 0.329). Conclusions: In our cohort, HER2 status was not significantly associated with pCR in a manner consistent with data published recently on TNBC. However, the prognostic impact of HER2-low expression among TNBC patients warrants further evaluation.

Potential Predictive and Prognostic Value of Biomarkers Related to Immune Checkpoint Inhibitor Therapy of Triple-Negative Breast Cancer.

As an aggressive subtype of breast cancer, triple-negative breast cancer (TNBC) is associated with poor prognosis and lack of effective therapy, except chemotherapy. In recent years, immunotherapy based on immune checkpoint (IC) inhibition has emerged as a promising therapeutic strategy in TNBC. TNBC has more tumor-infiltrating lymphocytes (TILs) and higher rate of mutation and programmed cell death ligand-1 (PD-L1) expression than other subtypes of breast cancer have. However, previous studies have shown that monotherapy has little efficacy and only some TNBC patients can benefit from immunotherapy. Therefore, it is important to identify biomarkers that can predict the efficacy of IC inhibitors (ICIs) in TNBC. Recently, various biomarkers have been extensively explored, such as PD-L1, TILs and tumor mutational burden (TMB). Clinical trials have shown that PD-L1-positive patients with advanced TNBC benefit from ICIs plus chemotherapy. However, in patients with early TNBC receiving neoadjuvant therapy, PD-L1 cannot predict the efficacy of ICIs. These inconsistent conclusions suggest that PD-L1 is the best to date but an imperfect predictive biomarker for efficacy of ICIs. Other studies have shown that advanced TNBC patients with TMB ≥10 mutations/Mb can achieve clinical benefits from pembrolizumab. TILs also have potential predictive value in TNBC. Here, we select some biomarkers related to ICIs and discuss their potential predictive and prognostic value in TNBC. We hope these biomarkers could help to identify suitable patients and realize precision immunotherapy.

Chemotherapy Decision-Making and Survival Outcomes in Older Women With Early Triple-Negative Breast Cancer: Evidence From Real-World Practice.

Data regarding chemotherapy options and benefits in older women with early triple-negative breast cancer (TNBC) are limited. Our study aimed to assess the effects of adjuvant chemotherapy on recurrence-free survival (RFS), breast cancer-specific survival (BCSS), and overall survival (OS) rates in elderly TNBC patients. Patients aged ≥65 years diagnosed with stage I-III TNBC (except T1aN0) between 2010 and 2016 were retrospectively included. Multivariate Cox regression was performed to minimize bias. A total of 177 patients were included with a median age of 69 years (range, 65-86), almost all had a Charlson Comorbidity Index of 0-2, and 127 (71.8%) received chemotherapy. Patients who received chemotherapy were younger, had more advanced-stage disease and had better ECOG performance status (P<0.05). Among the 127 patients who were administered chemotherapy, 45 (35%) received taxane plus carboplatin, 36 (28%) received anthracycline-and-taxane-based regimens, and 23 (18%) received taxane-based regimens. The regimen options differed based on patient age and tumour stage (P<0.05). Nearly 80% of the patients completed ≥6 cycles of chemotherapy, and half had their dosage decreased. After adjustment for confounding factors, patients who received ≥6 cycles of chemotherapy were found to have improved RFS rates (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.09-0.87; P=0.027), and receipt of chemotherapy (≥1 cycle) was associated with better BCSS (HR, 0.19; 95% CI, 0.04-0.97; P=0.046) and OS (HR, 0.26; 95% CI, 0.08-0.87; P=0.029) rates. These results support the considering the risk for recurrence and performing individualized assessments when determining the appropriate chemotherapy approach for older women with early TNBC.

Current and Future Role of Neoadjuvant Chemoimmunotherapy for Early Triple-Negative Breast Cancer: Which Way to Go Forward.

Immunotherapy has revolutionized previous triple-negative breast cancer (TNBC) treatment algorithms, prompting researchers and clinicians to consider the expansion of the role of immunotherapy in other settings, including the earlier stage of the disease (e.g., as neoadjuvant and adjuvant therapy). The role of chemoimmunotherapy have been assessed in some recently presented and published clinical trials, including the KEYNOTE-522, the IMpassion031, and the GeparNUEVO. In the current Editorial, we will provide a critical snapshot of these studies, exploring strengths and limitations of neoadjuvant chemotherapy in early TNBC.

Systemic Therapy De-Escalation in Early-Stage Triple-Negative Breast Cancer: Dawn of a New Era?

Simple SummaryTriple-negative breast cancer is a life-threatening disease, even when identified at early stages. Recent advances have allowed the improvement of life expectancy via a personalized approach with the addition of newer chemotherapies, immunotherapies, and targeted therapies, but at the cost of added side effects. It has become increasingly clear that not all patients need such aggressive treatment. Here, we provide an overview of emerging opportunities to use less toxic therapies in patients at lower risk of recurrence or with mutations that can be effectively targeted using novel approaches. We provide a comprehensive review of completed and ongoing clinical trials with information on how to best stratify these patients for treatments to obtain maximum benefit without unnecessary toxicities.Early-stage triple negative breast cancer (TNBC) has been traditionally treated with surgery, radiation, and chemotherapy. The current standard of care systemic treatment of early-stage II and III TNBC involves the use of anthracycline-cyclophosphamide and carboplatin-paclitaxel with pembrolizumab in the neoadjuvant setting followed by adjuvant pembrolizumab per KEYNOTE-522. It is increasingly clear that not all patients with early-stage TNBC need this intensive treatment, thus paving the way for exploring opportunities for regimen de-escalation in selected subgroups. For T1a tumors (≤5 mm), chemotherapy is not used, and for tumors 6–10 mm (T1b) in size with negative lymph nodes, retrospective studies have failed to show a significant benefit with chemotherapy. In low-risk patients, anthracycline-free chemotherapy may be as effective as conventional therapy, as shown in some studies where replacing anthracyclines with carboplatin has shown non-inferior results for pathological complete response (pCR), which may form the backbone of future combination therapies. Recent advances in our understanding of TNBC heterogeneity, mutations, and surrogate markers of response such as pCR have enabled the development of multiple treatment options in the (neo)adjuvant setting in order to de-escalate treatment. These de-escalation studies based on tumor mutational status, such as using Poly ADP-ribose polymerase inhibitors (PARPi) in patients with BRCA mutations, and new immunotherapies such as PD1 blockade, have shown a promising impact on pCR. In addition, the investigational use of (bio)markers, such as high levels of tumor-infiltrating lymphocytes (TILs), low levels of tumor-associated macrophages (TAMs), and complete remission on imaging, also look promising. In this review, we cover the current standard of care systemic treatment of early TNBC and review the opportunities for treatment de-escalation based on clinical risk factors, biomarkers, mutational status, and molecular subtype.

KEYNOTE-522, IMpassion031 and GeparNUEVO: changing the paradigm of neoadjuvant immune checkpoint inhibitors in early triple-negative breast cancer.

Stage I-III triple-negative breast cancer accounts for approximately 15-20% of new diagnoses of early breast cancer. Novel systemic treatment options have recently been assessed as part of the neoadjuvant approach, such as the addition of immune checkpoint inhibitors to cytotoxic chemotherapy. However, several questions remain unanswered, including the identification of predictors of response to immunotherapy in this setting, and further efforts aimed at identifying reliable predictors and clarifying the effective role of PD-L1 status, tumor mutational burden, tumor-infiltrating lymphocytes and other biomarkers are warranted. Herein we will provide an overview of recent clinical studies of neoadjuvant immune checkpoint inhibitors in patients with triple-negative breast cancer, especially focusing on the recently presented and published KEYNOTE-522, IMpassion031 and GeparNUEVO trials.

Programmed death receptor ligand-2 (PD-L2) bearing extracellular vesicles as a new biomarker to identify early triple-negative breast cancer patients at high risk for relapse

PurposeBased on the tumor-promoting features of extracellular vesicles (EV) and PD-L1/2-bearing EV subpopulations (PD-L1/2EV), we evaluated their potential as surrogate markers for disease progression or eligibility criteria for PD-1 immune checkpoint inhibition (ICI) approaches in early triple-negative breast cancer (TNBC).MethodsAfter enrichment of EV from plasma samples of 56 patients before and 50 after chemotherapy (CT), we determined levels of EV particle number and PD-L1/2EV by nanoparticle tracking analysis or ELISA and associated the results with clinical status/outcome and the presence of distinct circulating tumor cells (CTC) subpopulations.ResultsCompared to healthy controls, patients had a tenfold higher EV concentration and significantly elevated PD L2EV but not PD L1EV levels. The most important clinical implications were found for PD-L2EV. High PD-L2EV levels were associated with a significantly reduced 3-year progression-free and overall survival (PFS and OS). A loss of PD-L2EV after CT was significantly more prominent in patients achieving pathological complete response (pCR). Increased pre-CT PD-L2EV levels were found in patients having NOTCH1-positive or ERBB3-positive CTC. The presence of ERBB3-positive CTC combined with high pre-CT PD-L2EV resulted in a shorter PFS.ConclusionThis study highlights PD L2EV as a promising biomarker for risk assessment of TNBC patients and represents the basic for additional studies introducing PD-L2EV as an eligibility criterion for PD-1 ICI approaches.

Efficacy of Sequential Capecitabine on Adjuvant Chemotherapy of Triple-Negative Breast Cancer

This paper aims to evaluate the efficacy of capecitabine as extended adjuvant treatment after anthracycline and paclitaxel combined adjuvant chemotherapy for women with early triple-negative breast cancer (TNBC). The patients with early TNBC were randomly assigned to capecitabine sequential treatment for 4 cycles and without any sequential treatment in the control group after anthracycline and paclitaxel combined adjuvant chemotherapy. The primary end point was disease-free survival (DFS). The secondary end point was overall survival (OS). One hundred patients were enrolled in this study between June 2013 and February 2015. Median age was 49 years ranging from 25 to 66 years and treatment was well tolerance. The median follow-up time after random allocation was 58 months (range: 11–62 months). There was no significant difference in DFS and OS between the two groups (hazard ratio (HR) of DFS was 0.50; 95% CI, 0.24–1.05; P=0.066). Our study shows that although the addition of four cycles capecitabine after anthracycline and paclitaxel combining adjuvant chemotherapy does not improve DFS and OS, but the trend of DFS is improved. The possible reason is that the four-cycle treatment of capecitabine is not enough, and another possible reason is that the number of cases is not enough.

Abstract OT2-30-01: Nordictrip, a translational randomized phase-3study exploring the effect of the addition of capecitabine to carboplatinum-based chemotherapy in early “triple negative” breast cancer, ClinicalTrials.gov Identifier: NCT04335669

Abstract Background: A striking heterogeneity combined with an absence of highly efficient targeted treatments necessitates a continued effort to optimize the choice of chemotherapy for patients with triple negative breast cancer (TNBC). Neoadjuvant therapy has become the standard of care for high risk TNBC in order to potentially reduce breast and axillary surgery, start medical treatment early, allow genomic screening and guide post neoadjuvant therapy. Much attention is drawn to the use of immunotherapy in early TNBC, but there is also interesting data suggesting a potential to optimize the use of conventional chemotherapy. According to one meta-analysis including data from nine randomized controlled trials, the addition of platinum salts in the preoperative setting increases the pathologic complete response (pCR) rate in TNBC (Poggio 2018). A second meta-analysis, evaluating the effect of capecitabine in early breast cancer indicates an additional benefit from adding capecitabine to conventional chemotherapy in terms of an increased recurrence-free survival in the subset of TNBC (Mackelenbergh SABCS 2019). An adjuvant trial in TNBC suggests that the beneficial effect of capecitabine may be confined to patients with a non-basal like phenotype of TNBC (Lluch 2020), a subset that correlates with the homologous repair non-deficient subset which constitutes 41 % of TNBC in a mainly south Swedish population based cohort (Staaf 2019). The effect of capecitabine in platinum treated early TNBC is unknown. Objectives: We are conducting a multi-center randomized controlled trial evaluating the effect on the pCR rate by the addition of capecitabine to optimal platinum based and dose dense preoperative chemotherapy in early TNBC. Method: 820 patients (pts) with early TNBC stage 1 (≥20 mm) - 3 will be randomized 1:1 between two treatment arms A and B. A: Epirubicine Cyclophosphamide (EC) q2w x 4 followed by Carboplatin AUC 5 q3w with weekly paclitaxel x 12. B: Epirubicine Cyclophosphamide with capecitabine daily for two weeks (CEX) q3w x 4 followed by Carboplatin AUC 5 q3w with weekly paclitaxel x 12 The primary endpoint is pCR rate in the different treatment strata, and the primary translational endpoint will be the potential difference of treatment effect stratified for HRD-status in the primary tumor. Secondary endpoints include IDFS in subsets of TNBC, eg according to gene-expression-based subtypes of TNBC (Lehmann 2011, Burstein 2015), and germline mutation status of hereditary breast cancer genes. Tumor material for genotypig is collected at baseline, at surgery and optionally after two treatment cycles. Sequential blood samples are collected for tsDNA analysis during and after treatment termination. Results: The trial, which is a collaborative effort between the national breast cancer groups in the participating countries, has been postponed by the pandemic but is now recruiting according to plan. So far 56 patients out of 820 have been recruited at 15 sites in Sweden and Denmark. Additional Sites in Sweden, Denmark, Iceland and Finland are preparing to join the study. For update please see: www.NordicTrip.se; E-mail address: Nordictrip.onkologi@skane.se Citation Format: Niklas Loman, Barbro Linderholm, Johan Ahlgren, Siker Kimbung, Lina Zander, Heidi Grill Magnusson, Eva-Christin Kjellman, Ann Julia Raaberg, Maj-Britt Raaby Jensen, Åke Borg, Johan Staaf, Anders Ståhlberg, Pär-Ola Bendahl, Anne-Vibeke Laenkholm, Minna Tanner, Olöf Bjarnadóttir, Oskar Johannsson, Bent Ejlertsen, Henrik Lindman. Nordictrip, a translational randomized phase-3study exploring the effect of the addition of capecitabine to carboplatinum-based chemotherapy in early “triple negative” breast cancer, ClinicalTrials.gov Identifier: NCT04335669 [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 OT2-30-01.

Abstract ES5-2: Optimizing the management of early stage TNBC

Abstract The recent approvals of the immunotherapeutic agent pembrolizumab, the antibody-drug conjugate sacituzumab govitecan and the PARP inhibitors olaparib and talazoparib for select patients with metastatic triple negative breast cancer (TNBC) have spurred interest in evaluating these and other novel agents in patients with earlier stage disease. For the last several decades, a standard approach to treating early stage TNBC was to administer neoadjuvant chemotherapy, most often an anthracycline/taxane-based regimen. Pathologic complete response (pCR) rates generally ranged 30-40%. Trials such as CALGB 40603, GeparSixto and BrighTNess demonstrated that the addition of carboplatin to an anthracycline and taxane based chemotherapy could increase the pCR rates (53-58%). At the most recent ESMO conference, the BrighTNess investigators reported that the addition of carboplatin improved event free survival (EFS) after a median follow-up of 4.5 years. For patients not experiencing a pCR, the Create-X trial showed benefit of capecitabine in the adjuvant setting.As of August 2021, there is a new standard for treating early stage TNBC. Specifically, based on the KEYNOTE-522 trial, pembrolizumab, in combination with chemotherapy, is FDA approved for this indication. KEYNOTE-522 enrolled over 1170 stage 2-3 TNBC patients and randomized them to chemotherapy +/- pembrolizumab. The most recent report showed the trial met it’s co-primary endpoints of improved pCR (63% vs 56%) and EFS (84.5% vs 76.8%) after a median follow-up of 39 months. Importantly, the benefit was regardless of the PD-L1 status of the patient’s tumor. With the approval of pembrolizumab comes a number of questions: 1) which patients should receive this regimen which is associated with immune-related toxicities, some of which are lifelong, 2) what is the optimal chemotherapy backbone, 3) is a full year of pembrolizumab required and 4) are there other biomarkers to be explored that may predict response to therapy or the development of toxicity? Other studies either have or are evaluating other targeted agents in the preoperative setting for early stage TNBC. In a small study of 20 BRCA mutation carriers treated preoperatively with single agent talazoparib, investigators reported a pCR rate of 53%. A study looking at sacituzumab monotherapy in the preoperative setting has completed accrual and the results are awaited. These two trials begin to address the question of whether we can identify an “achilles” heel in TNBC and if so, will targeting it improve patient outcomes. Good correlative studies that provide improved understanding of the impact of these therapies on the TNBC microenvironment will help inform the next generation of trials; likely combination therapies.There is also the question of adjuvant therapy, particularly for those that do not experience a pCR with preoperative therapy. As stated above, the CREATE-X trial supports the use of capecitabine in patients with residual disease, however EA1131 demonstrated that outcomes are still poor for this population. More recently, for patients with BRCA-mutated cancers, the OlympiA trial showed benefit to a year of adjuvant olaparib. There is also growing interest in whether patients with residual disease who are at highest risk for recurrence can be identified using technologies looking for cell-free DNA to find those with minimal residual disease. Historically we’ve thought about TNBC for what it’s not – it is not ER, PR or HER2 positive. With multiple studies now showing benefit of specific agents in TNBC, the next several years will provide an opportunity to more extensively dissect triple negative tumors and their. microenvironment. This will allow us to learn what TNBC “is”, and which of likely multiple different therapeutic strategies will be best applied to which patients. Citation Format: E Mittendorf. Optimizing the management of early stage TNBC [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 ES5-2.

Abstract P1-12-04: The impact of chemotherapy in elderly early triple negative breast cancer: A population based study from the SEER database

Abstract Introduction: The management of senile breast cancer is still controversial, especially chemotherapy. Therefore, we conduct an analysis of the impact of chemotherapy and establish prediction models of prognosis in elderly early TNBC by using machine learning. Methods: We enrolled 4,696 patients from SEER database according to the following criteria: female; year of diagnosis from 2010 to 2016; age of diagnosis ≥ 70 years; invasive ductal carcinoma as the only primary malignant cancer; stage I-III; TNBC subtype. The PSM method was utilized to reduce covariable imbalance. Univariable and multivariable analyses were used to compare BCSS and OS. KNN, CatBoost, decision tree, random forest, Gradient Boost, LightGBM, neural network models, SVM, XGBoost and logistic regression models were developed to predict the 5-year OS and BCSS for patients in the chemotherapy group. Results: Compared to matched patients with no-chemotherapy, multivariate analysis showed a better survival in matched patients with chemotherapy(BCSS:HR = 0.594,95%CI = 0.479-0.737,p &amp;lt; 0.001; OS:HR = 0.532,95%CI = 0.446-0.635,p &amp;lt; 0.001). Stratified analyses by age and stage was also conducted to discriminate the patients benefited from chemotherapy. Chemotherapy didn’t lowered the risk of cancer-specific mortality and all-cause mortality in stage I cohort (70-79 years, BCSS, HR=1.058, 95% CI=0.609-1.838, p=0.841; OS HR=0.721, 95% CI=0.478-1.086, p=0.117; 80+ years, BCSS, HR=0.210, 95% CI=0.005-8.920, p=0.414; OS HR=0.458, 95% CI=0.048-3.918, p=0.458). But patients diagnosed with stage II can benefit from chemotherapy (70-79 years, BCSS, HR=0.628, 95% CI=0.424-0.932, p=0.021; OS HR=0.538, 95% CI=0.386-0.749, p&amp;lt;0.001; 80+ years, BCSS, HR=0.413, 95% CI=0.230-0.744, p=0.003; OS HR=0.416, 95% CI=0.260-0.667, p&amp;lt;0.001). We observed similar phenomena in the stage III cohort. We further investigated the effects of tumor and nodal status in stage II cases between the two groups. We found that chemotherapy was a better prognostic indicator for patients with T2N0M0 and stage IIb (T2N0M0, BCSS, HR=0.420, 95% CI=0.261-0.675, p&amp;lt;0.001; OS HR=0.0.361, 95% CI=0.243-0.536, p&amp;lt;0.001; stage IIb, BCSS, HR=0.752, 95% CI=0.454-1.246, p=0.269; OS HR=0.640, 95% CI=0419-0.978, p=0.039), but not for T1N1M0 (BCSS, HR=0.778, 95% CI=0.249-2.432, p=0.666; OS HR=1.072, 95% CI=0.458-2.508, p=0.872). For patients with grade I and II, no statistical survival differences were identified between chemotherapy and no-chemotherapy patients(BCSS, HR=0.781, 95% CI=0.445-1.368, p=0.387; OS HR=0.802, 95% CI=0.512-1.256, p=0.335). While for patients with grade III, the chemotherapy patients demonstrated a better prognosis than no-chemotherapy patients (BCSS, HR=0.558, 95% CI=0.440-0.707, p&amp;lt;0.001; OS, HR=0.492, 95% CI=0.405-0.599, p&amp;lt;0.001). Ten models mentioned above were conducted to predict the 5-year OS and BCSS for patients in the chemotherapy group. On average, the accuracy was 0.885 on 5-year BCSS and 0.858 on 5-year OS. The average precision of the examined ten algorithms was 0.880 on 5-year BCSS and 0.862 on 5-year OS. Similarly, the average sensitivity was 0.981 on 5-year BCSS and 0.971 on 5-year OS. There was average F1 score of 0.932 on 5-year BCSS and 0.913 on 5-year OS. In terms of the AUC, the highest AUC was observed for the LightGBM. Considering all the parameters above, the LightGBM outperformed all other algorithms. Conclusion: For stage I, T1N1M0, grade I and grade II elderly early triple negative invasive ductal carcinoma patients, chemotherapy could not improve OS and BCSS. Therefore, de-escalation therapy might be appropriate for selected patients. The LightGBM is practical and trustful to predict the 5-year OS and BCSS for patients in the chemotherapy group. Citation Format: KaiYan Huang, Jie Zhang, YuShuai Yu, YuXiang Lin, ChuanGui Song. The impact of chemotherapy in elderly early triple negative breast cancer: A population based study from the SEER database [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-12-04.

Abstract PD10-01: The PEARL trial: Pre-operative pembrolizumab with radiation therapy in early stage triple negative breast cancer

Abstract Background: Anti-PD(L)1 in addition to neoadjuvant chemotherapy (NAC) can achieve pathologic complete response (pCR) rates of up to 65% in patients with early stage triple negative breast cancer (TNBC). However, patients with non-pCR can have dismal prognosis. Innovative strategies that render the tumor microenvironment more sensitive to anti-PD(L)1 may confer benefit. Preclinical studies have shown that hypofractionated radiation therapy (RT) delivered to an in-situ breast tumor, when combined with immune checkpoint blockade, stimulates anti-tumor immune responses and induces long-term, tumor-specific memory. Here, we report the first results of a phase II study that established the feasibility and efficacy of this approach in the pre-operative treatment setting for TNBC. Methods: Fifty patients with stage I-III TNBC, defined as ER&amp;lt;10%,PR&amp;lt;10%, HER2-negative, were enrolled between 12/17-4/21. Study treatment consisted of one cycle (C1) of pembro (200 mg iv q 3wks), followed by cycle 2 (C2) of pembro + RT (24Gy) delivered to a breast primary, followed by NAC regimen per MD choice, surgery and adjuvant therapy. Paired tumor biopsies and blood were collected at 3 serial time points: 1) baseline (pre-treatment); 2) after pembro C1; 3) after pembro C2 + RT (prior to initiation of NAC). All patients received breast and axillary surgery and postoperative RT to the chest wall and regional lymph nodes. Dual primary endpoints were: 1) feasibility, defined by the number of patients who did not necessitate a &amp;gt;4-week delay in initiating NAC after pembro C2 + RT; 2) change in tumor infiltrating lymphocyte (TIL) score. Secondary endpoints included pCR, defined as ypT0/TisypN0, in addition to toxicity and cosmesis evaluations. Results: To date, 50 patients are evaluable with a median follow up of 12 months (range 6-12). Median age of cohort is 55y (range 26-76). The majority (92%) were clinical stage II; 2% stage I and 6% stage III. 34% of the cohort had biopsy-proven, node positive disease. All patients received a taxane, 52% carboplatin and 74% anthracycline. 12% did not complete the planned course of NAC due to toxicities. No patients experienced a delay in initiating NAC. 50% received breast-conserving surgery and 50% mastectomy. Grade 1 or 2 toxicities consisted of fatigue (76%), nausea (66%), maculopapular rash (32%), diarrhea (38%), colitis (2%), hypothyroidism (8%) and peripheral neuropathy (40%). Four patients had grade 3 toxicities that were attributable to pembro: hyponatremia(1), colitis (1), adrenal insufficiency(1) and pneumonitis (1). Three patients had grade 4 neutropenia which were not attributable to pembro. The overall rate of pCR was 74% (37/50). Among the 13 patients with non-pCR, 0% were RCB 1, 16% RCB 2 and 10% RCB 3. Among the 17 N+ patients, 13 converted to ypN0, 1 ypN1mic and 3 ypN1a. No patients progressed during treatment. Changes in TIL count, PD-L1 and other biomarkers after pembro +/- RT and their association with treatment response, will be presented at the meeting. Conclusions: The novel combination of pre-operative pembro followed by the addition of RT to pembro prior to NAC is not only feasible, but also achieves pCR rates that are higher-than-expected compared to the pembro arm of KEYNOTE-522. AEs were consistent with known safety profiles of each agent. If confirmed by larger, randomized studies, this combination will be paradigm-changing for the treatment of TNBC. Citation Format: Heather L McArthur, Stephen Shiao, Scott Karlan, Reva Basho, Farin Amersi, Michele Burnison, Amin Mirhadi, Alice Chung, Cathie T Chung, Catherine Dang, Heather Richardson, Armando E Giuliano, Nimmi Kapoor, Brigid Larkin, Hector Godinez, Samantha A Dunn, Negin Habibi Khameneh, Simon Knott, Philomena McAndrew, Monica Mita, Dorothy J Park, Christina Abaya, Jonathan H Chen, Amy Ly, Veerle Bossuyt, Alice Ho. The PEARL trial: Pre-operative pembrolizumab with radiation therapy in early stage triple negative breast cancer [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 PD10-01.

Abstract P2-12-15: Neoadjuvant liposomal doxorubicin and carboplatin is effective and tolerable for the treatment of early stage triple negative breast cancer

Abstract Background: The addition of neoadjuvant platinums to standard chemotherapy regimens for triple negative breast cancer (TNBC) improves rates of pathologic complete response (pCR). Our prior trial combining carboplatin (CAR) with liposomal doxorubicin (DOX) for metastatic TNBC showed good response rates with minimal side effects and allows for higher platinum dosing. We hypothesized that the doublet of DOX+CAR is effective and tolerable in the neoadjuvant setting for TNBC and tumor genomics may identify biomarkers of complete response and actionable targets. Methods: A phase II single arm trial was conducted for patients (pts) diagnosed with stage II-III TNBC. Patients received 4 cycles of neoadjuvant carboplatin (AUC 5) and liposomal doxorubicin (30mg/m2) administered every 28 days, then underwent definitive breast surgery followed by 12 weeks of adjuvant paclitaxel 80 mg/m2 administered weekly. Primary and secondary clinical endpoints were rate of pCR and two year recurrence free survival (RFS) and overall survival (OS), respectively. Cardiac safety of the combination was assessed. Fresh residual tumor samples were obtained at time of surgery for generation of patient derived xenografts (PDX). Whole genome sequencing (WGS) and RNA sequencing will be performed to evaluate specific patterns of small-variant mutations and patterns of structural variants to identify which patients are likely to have pCR. Results: From 2/2015 to 6/2021, 62 pts were enrolled, 8 pts withdrew consent either prior to treatment or completion of neoadjuvant therapy and/or surgery. Median age of the cohort was 55.4 years. There was high participation by under-represented groups: 17.0% African American, 20.8% Asian, 13.2% Hispanic. Most histologies were invasive ductal carcinoma, but included apocrine, pleomorphic lobular, and metaplastic subtypes. 53 pts completed all 4 cycles of neoadjuvant DOX+CAR, followed by definitive surgery; 1 pt progressed after 1 cycle and proceeded to surgery thereafter. 30.2% (16) pts achieved pCR, and residual cancer burden (RCB) will be reported in patients with residual disease. Of the 53 pts who completed 4 cycles of treatment, 5 pts progressed (recurrence or death) within two years from time of surgery (4 distant and 1 local recurrence), yielding the 2-year recurrence-free-survival rate of 90.3% (95%CI 81.0%, 99.6%). The most common toxicities during DOX+CAR were grade 1 fatigue in 50 pts (92.6%), grade 1 anemia in 44 pts (81.5%), and grade 3/4 neutropenia in 16 pts (29.6%); these pts received GCSF support with subsequent cycles; febrile neutropenia occurred in 1 pt (1.9%) in this group. Only 10 pts (18.5%) had grade 1 alopecia, 5 pts (9.3%) had grade 2 alopecia, 2 pts (3.7%) had grade 3 thrombocytopenia. There were no delays in treatment due to cardiotoxicity or complications from surgical healing. Of the 37 pts who had residual disease, PDX was attempted in 21 pts, and 16 (76%) PDX were established, including those for 4 patients experiencing recurrence. WGS and RNA sequencing data from pre-treatment and residual disease samples will be analyzed and reported.Conclusion: 4 cycles of neoadjuvant DOX+CAR achieved rate of pCR similar to standard regimens and has good tolerability. Post chemotherapy PDX is feasible and may help identify targeted approaches for patients with resistant disease. These results warrant further evaluation of this combination for early stage TNBC. Citation Format: Nancy Chan, Shou-en Lu, Yue Wang, Gregory M Riedlinger, Coral Omene, Mridula George, Jyoti Malhotra, Maria Kowzun, Firas G Eladoumikdachi, Lindsay B Potdevin, Shicha Kumar, Kant Matsuda, Shruti Desai, Nayana Patel, Deborah L Toppmeyer, Shridar Ganesan, Kim Hirshfield. Neoadjuvant liposomal doxorubicin and carboplatin is effective and tolerable for the treatment of early stage triple negative breast cancer [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 P2-12-15.

Abstract ES6-3: Immunotherapy vs Capecitabine for Triple Negative Breast Cancer

Abstract Immunotherapy vs capecitabine for triple negative breast cancer. Educational session. Sherene Loi, MD, PhDPeter MacCallum Cancer Centre, Melbourne, Australia. Neoadjuvant treatment is now standard of care for the majority of early stage triple negative breast cancer (TNBC), with the achievement of non-pathological complete response (pCR) the main indicator to escalate treatment. Until recently only capecitabine was used in this setting. 2021 has seen reporting of the OlympiA adjuvant study, which reports major benefits for olaparib in germline BRCA positive TNBC patients, though a minority. KEYNOTE522 has now set the scene for incorporating neoadjuvant pembrolizumab with chemotherapy in early stage TNBC, with significantly improved event free survival, particularly those that do not achieve pCR. In this talk I will examine how we can rationally think about treating these patients with the available options. Citation Format: S Loi. Immunotherapy vs Capecitabine for Triple Negative Breast Cancer [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 ES6-3.

Abstract P2-09-18: Use of navigators to identify breast cancer patients for genetic counseling and testing: A quality improvement project

Abstract The value of genetic counseling and testing to cancer prevention, early detection, and treatment options to ensure optimal outcomes is widely acknowledged by providers, payers and patients. However, many individuals who should receive genetic counseling are never offered this service. All patients with early onset (&amp;lt;=age 45), triple negative (&amp;lt;=60) and metastatic HER2 negative breast cancer should be offered genetic counseling and testing (GC/GT) per National Comprehensive Cancer Network guidelines. A quality improvement project to actively identify and offer genetic counseling to all women with early onset, triple negative and metastatic breast cancer was implemented.Baseline information on the number of early onset (&amp;lt;=45), triple negative and metastatic HER2 negative breast cancers diagnosed January 2018-June 2019 was collected and cross-referenced with the Cancer Genetics Risk Assessment patient database and the electronic health record (EHR) to see how many had GC/GT in our department or the breast surgeons’ office. We developed questions for an electronic screening tool used by the navigation team when meeting with patients for the first time, screening for personal or family history criteria that would flag patients at increased risk for hereditary cancer. If any questions were flagged, the patient was asked by the navigator if they would be interested in a genetic counseling appointment to consider genetic testing. Training was provided to the navigation team so that they could answer basic questions, bi-weekly meetings were set up to discuss patients, and a flier and informational videos were made available to patients who wanted more information about GC/GT. If a patient was agreeable to genetic counseling, an automated email was triggered to the genetics team, who contacted the patient for an appointment. A standing order was obtained from willing breast surgeons and oncologists within our network to streamline the referral process. In the 18-month baseline period, there were 126 patients diagnosed with early onset, 36 with triple negative &amp;lt;=60 and 30 with metastatic HER2 negative breast cancer. Of these, 57.1% of early onset, 66.7% triple negative and 3.3% of those with metastatic breast cancer had documentation of GC/GT. A paper screening tool was implemented in July 2019 with implementation of an electronic version in November 2019. In the 18-month intervention period, there were 100 patients diagnosed with early onset, 39 with triple negative and 22 patients with metastatic breast cancer. Of these, 86% of early onset, 87.2% of triple negative and 31.8% of metastatic breast cancer patients had documented GC/GT.A limitation of this project is that some patients leave the system to be treated elsewhere after diagnosis and some may have been tested in their private practitioner’s office that does not connect with our EHR. Additionally, some may have been offered GC/GT but declined or were unwilling/unable to complete an appointment. Finally, the pandemic likely had an impact on this project, since fewer women were undergoing mammography screening due to COVID-19 restrictions, resulting in fewer diagnoses of breast cancer. By leveraging the navigation team’s interaction with breast cancer patients, we were able to improve identification and referral of more patients with early onset, triple negative &amp;lt;=60 and metastatic HER2 negative breast cancer for GC/GT. One barrier to genetic counseling that has been previously identified is a lack of physician referral. Active engagement with a breast navigator can circumvent this barrier. De-identified aggregate data from this quality improvement project was shared with the Association for Community Cancer Centers as part of a larger project, supported by a grant from Pfizer. Citation Format: Stephanie A. Cohen, Dawn Nixon. Use of navigators to identify breast cancer patients for genetic counseling and testing: A quality improvement project [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 P2-09-18.

Abstract PD10-03: BEGONIA: Phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC): Results from Arm 1 D + paclitaxel (P), Arm 2 D+P + capivasertib (C), and Arm 5 D+P + oleclumab (O)

Abstract Background: Chemotherapy, together with immune checkpoint inhibitors, improves outcomes vs chemotherapy alone for patients (pts) with metastatic (m)TNBC PD-L1+ disease. Most of these pts progress within a year. In a previous study, D (anti-PD-L1) combined with chemotherapy enhanced antitumor immune responses in early TNBC (Loibl. Ann Oncol 2019). In TNBC, activation of the PI3K/AKT/PTEN pathway and high CD73 expression are common. BEGONIA is an ongoing 2-part, multicenter, multi-arm, open-label platform study, evaluating safety and efficacy of D or D+P combined with novel therapies as first-line treatment for mTNBC (NCT03742102). Preliminary results from 2 arms were presented at ASCO 2021 (Abstract #1023). Here, we report results from Arm 1 D+P, Arm 2 D+P+C, and Arm 5 D+P+O. C is an oral, selective, ATP-competitive catalytic inhibitor of all 3 AKT isoforms, and O is a mAb targeting CD73. Methods: Eligible pts had untreated, unresectable, locally advanced or metastatic TNBC. In Arms 1 and 5, pts received D 1500 mg IV Q4W + P 90 mg/m2 IV day (d)1, d8, d15 of every cycle. Pts in Arm 5 also received O 3000 mg IV on d1 and d15 for the first 2 cycles, then Q4W. In Arm 2, pts received D 1500 mg IV Q4W + P 80/90 mg/m2 IV in 4-week cycles (d1, d8, d15, 1 week off) + C 400 mg BID in 4-week cycles (d2-5 × 3 weeks, 1 week off). Primary objectives were safety and tolerability. Secondary endpoints included objective response rate (ORR) and duration of response. Tumors were assessed Q8W per RECIST v1.1. The first 6 pts treated in Arms 2 and 5 were evaluated for dose-limiting toxicities (DLTs), with additional pts enrolled if treatment was tolerated. PD-L1 expression was assessed retrospectively. Previously presented data from Arm 1 D+P, are included for reference (Schmid. ASCO 2021, #1023). Results: In Arm 2 (data cutoff Mar 2021), 30 pts received D+P+C (15 P[80], 15 P[90]; total 13 ongoing); 2 pts (6.7%) discontinued all treatment due to AEs. The rates of dose delays were 13 pts (43%) for D and 15 (50%) for P; dose interruptions were 1 (3%) for D, 12 (40%) for P, 15 (50%) for C; dose reductions were 12 (40%) for P and 14 (47%) for C. Treatment-related (tr)SAEs and G3/4 trAEs were experienced by 7 (23%) and 22 (73%) pts. In Arm 5 (data cutoff Sep 2020), 33 pts received D+P+O (14 ongoing); no pts discontinued due to AEs. The rates of dose delays were 13 pts (39%) for D, 10 (30%) for P, 10 (30%) for O; dose interruptions were 2 (6%) for D, 10 (30%) for P, 3 (9%) for O; and dose reductions were 12 (36%) for P. trSAEs and G3/4 trAEs were experienced by 1 (3%) and 5 (15%) pts. In both arms, there were no DLTs or deaths due to AEs. The Table presents follow-up time and efficacy outcomes for Arms 1, 2, and 5. Responses were observed regardless of PD-L1 expression. The potential value of mutations in the PI3K pathway and CD73 expression as predictive biomarkers will be discussed for Arms 2 and 5, respectively. Updated data for Arm 1 will be presented. Conclusions: The safety profiles of triplet combinations in Arms 2 and 5 were consistent with the individual agents; however, in Arm 2, there was a relatively high rate of G3/4 trAEs but a low discontinuation rate for AEs. Although BEGONIA was not designed to compare activity across arms and numbers were small, the ORR of each triplet therapy was numerically similar to D+P. Biomarker analysis may elucidate pts that benefit from the combination of C or O with D+P. Funding: AstraZeneca Table. Efficacy outcomes in Arms 1, 2, and 5 of BEGONIAArm 1Arm 2Arm 5D+P N=23D+P(80)+C n=15D+P(90)+C n=15All D+P+C N=30D+P+O N=33Duration of follow-up at data cutoff, months, median (range)16.6 (8.5-19.8)6.7 (2-9)16.8 (6-21)8.2 (2-21)8.6 (4.1-14.6)Confirmed ORR, n (%)13 (56.5)8 (53.3)8 (53.3)16 (53.3)15 (45.5)95% CI34.5-76.826.6-78.726.6-78.7NC28.1-63.3CR, n10111PR12871514SD (Unconfirmed PR)7 (3)6 (2)4 (2)10 (4)13 (4)PD31345Percentage with ongoing response at data cutoff53.8%75.0%25.0%50.0%66.7%Arm 1 data cutoff was Sep 2020. C, capivasertib; CI, confidence interval; CR, complete response; D, durvalumab; NC, not calculable; O, oleclumab; ORR, objective response rate; P, paclitaxel; PD, progressive disease; PR, partial response; SD, stable disease. Citation Format: Peter Schmid, Zbigniew Nowecki, Seock-Ah Im, Wei-Pang Chung, Simon Lord, Anne Armstrong, Cynthia X Ma, Robert Huisden, Ross Stewart, Rakesh Kumar, Gaia Schiavon, Hannah Dry, Ana Nunes, Kyung Hae Jung, Yeon Hee Park. BEGONIA: Phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC): Results from Arm 1 D + paclitaxel (P), Arm 2 D+P + capivasertib (C), and Arm 5 D+P + oleclumab (O) [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 PD10-03.

Abstract PD11-08: Associations of baseline breast MRI metrics and immune infiltration with chemotherapy response in triple negative breast cancer

Abstract Introduction: In triple-negative breast cancer (TNBC), both response to neoadjuvant chemotherapy (NAC) and the degree of pre-treatment (pre-tx) tumor immune infiltration as defined by tumor-infiltrating lymphocytes (TILs) are prognostic. Improving NAC response prediction in early TNBC would provide the opportunity to consider adjustments to the NAC regimen prior to initiating therapy. Breast magnetic resonance imaging (MRI) enables noninvasive whole-tumor measurement of microenvironment features. We investigated the value of pre-tx MRI metrics in addition to TILs for the prediction of NAC response in early TNBC patients. Methods: Women with Stage I-III TNBC who underwent pre-tx clinical breast MRI and NAC at our institution (2005-2019) were retrospectively identified. Response to NAC was noted, with pathologic complete response (pCR) defined as no residual invasive cancer present within the breast. When tissue was available, diagnostic biopsy was used to quantify pre-tx TILs as deciles from 10-100% by a breast pathologist. Patients underwent pre-tx breast MRI on either a 1.5T or 3T scanner including diffusion-weighted (DW-) and dynamic contrast-enhanced (DCE-) MRI. From DCE-MRI, tumor longest diameter (LD) and T stage (1-4), as well as contrast kinetics including percent enhancement (PE) at 2 minutes post-contrast and signal enhancement ratio (SER) were determined. Tumor peak PE and peak SER (representing the highest mean PE and SER, respectively, for 3×3 voxel subregions) and functional tumor volume (FTV, tumor volume exhibiting PE ≥ 50%) were calculated. Mean apparent diffusion coefficient (ADC) was calculated from DW-MRI. TIL levels and imaging features were compared between pCR and non-pCR groups by Wilcoxon rank sum test and performance for prediction of pCR was evaluated using areas under the curve (AUC) measures from receiver operating characteristic curve analysis. Results: 115 TNBC patients (median age: 49, range 26-79 years) were evaluated, of which 45 (39%) achieved pCR. The majority received an anthracycline-containing regimen. Pre-tx TILs (evaluated in N=60 with available biopsy specimens) ranged from 10% to 80% (median, 10%) and were significantly higher in pCR vs. non-pCR patients (p = 0.02, AUC = 0.63). Pre-tx lesion size on imaging was predictive of response (Table 1), with pCR patients having significantly lower LD (p &amp;lt; 0.01, AUC = 0.68) and FTV (p = 0.01, AUC = 0.67). Peak PE was also associated with response, significantly lower in pCR patients (p = 0.04, AUC = 0.62), while SER and ADC were not (p &amp;gt; 0.05). Stratifying by T stage, both peak PE (p = 0.03) and FTV (p = 0.05) were predictive of response in T1/T2 patients, while no imaging metrics reached significance in T3/T4 patients. Discussion: In a large cohort of TNBC patients undergoing NAC, measures of tumor size and immune infiltration were strongly predictive of NAC response. Preliminary results suggest that baseline peak PE and FTV are associated with NAC response, particularly in earlier stage TNBC patients. These findings support the utility of imaging and TILs assessments to predict response in TNBC and potentially guide NAC regimens for improved outcomes. Future work will extend these analyses to assess the value of changes in imaging metrics over the course of NAC to predict response. Acknowledgments: NIH P30CA015704, R01CA248192, and Roger E. Moe Fellowship, ASCO/CCF Hayden Family Foundation Young Investigator Award in Breast Cancer Summary of imaging characteristics across TNBC cohort. Values indicate mean (standard deviation).Whole cohort. N=115T1/T2. N=80T3/T4. N=35pCR. N=45non-pCR. N=70pAUCpCR. N=39non-pCR. N=41pAUCpCR. N=6non-pCR. N=29pAUCLongest dimension (mm)34 (15)50 (27)&amp;lt;0.010.6829 (11)31 (10)0.410.5561 (6)76 (20)0.060.75FTV (cm3)14.7 (17.0)31.2 (43.4)0.010.6710.4 (11.0)19.0 (20.2)0.050.6446.1 (24.5)52.0 (58.0)0.720.57Peak SER1.77 (0.26)1.78 (0.23)0.960.501.76 (0.26)1.79 (0.23)0.690.531.91 (0.19)1.78 (0.26)0.270.68Peak PE (%)234 (61)268 (69)0.040.62237 (61)275 (71)0.030.66247 (70)256 (63)1.000.5ADC(×10-3 mm2/s)1.19 (0.29)1.31 (0.36)0.180.581.16 (0.28)1.24 (0.30)0.390.561.40 (0.30)1.4 (0.43)0.900.48 Citation Format: Anum S Kazerouni, Laura C. Kennedy, Michael Hirano, Bonny Chau, Debosmita Biswas, Shaveta Vinayak, Matthew J. Nyflot, Habib Rahbar, Suzanne Dintzis, Savannah C. Partridge. Associations of baseline breast MRI metrics and immune infiltration with chemotherapy response in triple negative breast cancer [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 PD11-08.