TNBC Group Research Articles

Evaluation of TRPS1 as a Diagnostic Marker for Breast Carcinoma

Abstract Background Breast cancer (BC) is a very important health challenge worldwide. It is the leading cause of global cancer incidence and the leading cause for cancer related mortality in women. BC is a disease with high metastatic potential always a suspect in the differential diagnoses of metastatic carcinoma of unknown primary. Based on the expression of ER, PR, Her2 BC is categorized into molecular subtypes as luminal (A&B), Her2-postive and triple negative (TNBC) subtypes. TNBC is the most aggressive form with high tendency for metastasis and overall poorer clinical behavior. Diagnosis of metastatic TNBC breast cancer is usually a diagnostic dilemma due to absence of sensitive and specific immunohistochemical marker for breast origin. Trichorhinophalangeal syndrome-1 (TRPS1) is a recently discovered breast marker with high expression in different molecular groups especially TNBC, making it a potential useful tool for diagnosis of BC. Objective To evaluate the immunohistochemical expression of TRPS1 in breast carcinoma as a highly sensitive and specific marker for breast carcinoma, especially for TNBC. Methods The current study was conducted retrospectively on 80 cases of invasive breast carcinoma as archived formalin fixed paraffin embedded blocks obtained the Pathology Department lab of Ain Shams University Hospitals (2019-2023). The cases included in the current study were divided into 3 groups; Group 1: included 25 Luminal cases, Group 2: included 20 Her-2 positive cases and Group 3: included 35 TNBC cases. Data concerned with gender, age and type of procedure were obtained from the electronically archived reports. The histopathological data were re-examined microscopically by at least two authors. After then, the expression of TRPS1 was evaluated in different molecular groups, followed by statistical evaluation of the obtained results. Results TRPS1 was expressed in 88.8% of the studied cases. No statistically significant relationship between TRPS1 expression and the histopathological subtype, tumor size, tumor grade, lymph node status nor in-situ duct component. TRPS1 high score was detected in 66.3% of the studied cases. TRPS1 showed high expression in different molecular groups, as it was detected in 96% of luminal group, 85% of Her2-positive group and 85.7% of TNBC group. These differences were not statistically significant. Conclusion TRPS1 is a sensitive marker for all molecular subtypes of breast cancer. It might be a valuable addition to determine breast origin in clinical practice especially for TNBC.

The i2b2 Temporal Data-Mining Solution for Automated Reconstruction of Different Breast Cancer Patterns of Care over a Decade of Observation

Background: In oncology, Patterns of Care (PoC) provide a detailed overview of all cancer-treatment interventions and recapitulate the entire patient’s journey. While manual-chart PoC reviewing is time-consuming, the use of Electronic Health Records (EHRs) enables the creation of data-mining solutions to automatically reconstruct the whole cancer trajectory with different granularity. Methods: We tested the ability of the i2b2 (Informatics for Integrating Biology and Bedside) solution to support the automatic reconstruction of the PoC for consecutive and unselected HER2+ and TNBC breast cancer patients through a retrospective EHRs analysis over a decade of observations. Results: From 2008 to 2017, 561 HER2+ and 412 TNBC patients were retrospectively identified by i2b2 platform at the Papa Giovanni XXIII Hospital in Bergamo. Most patients, 74.3% in the HER2 group and 71.8% in the TNBC group, received a (neo) adjuvant chemotherapy, with anti-HER2 drugs whenever indicated. Among the HER2 cohort, the 5-year Time to Treatment Change (TTC) and Overall Survival (OS) were 69.4% and 77.4% respectively, with 25% of patients receiving up to 3 lines of treatment in metastatic setting. Among the TNBC cohort, the 5-year TTC and OS were 59.3% and 69.4% respectively, with only 2% of patients receiving active treatment as third line of therapy. The consistency of the automated PoC reconstruction had to be reviewed in 1/3 of cases to clean conflicting data. Conclusion: The i2b2 solution has the potential to provide a retrospective, automated reconstruction of the different PoC, with limited manual-chart review refinement and might contribute to support investigations in the field of real-world data.

Abstract PS04-02: BRCA testing and PARP inhibitor utilization in real-world HER2-negative metastatic breast cancer

Abstract Background: PARP inhibitors (PARPi) have demonstrated progression-free survival benefits vs. chemotherapy in patients (pts) with metastatic breast cancer (mBC) and germline BRCA mutations (gBRCAm). NCCN guidelines recommend that all pts with mBC are offered gBRCAm testing to aid in systemic treatment decisions with PARPi. Understanding real-world gBRCAm testing patterns and PARPi use would be beneficial for improving clinical outcomes of pts with gBRCAm mBC. Methods: This retrospective cohort study identified pts ≥ 18 years old with HER2-negative mBC, diagnosed from 2014 to 2022 (US Flatiron Electronic Health Record database). gBRCAm testing patterns in mBC over time were examined by BC subtype (hormone receptor-positive [HR+] or triple-negative breast cancer [TNBC]) and disease stage at diagnosis [de novo or recurrent]). Timing of gBRCAm testing and subsequent initiation of first-line or later PARPi in pts with gBRCAm HR+ and TNBC mBC was assessed in pts diagnosed after 2018 when PARPi were approved in mBC. Prevalence of gBRCAm was calculated overall and by mBC subtype. Demographic and clinical characteristics were described by gBRCAm testing and PARPi initiation (yes/no). Real-world overall survival (OS) by PARPi use since mBC diagnosis was estimated using the Kaplan-Meier method and a log-rank test. Results: Of 15,006 total pts, 4654 (31.0%) had a gBRCAm test. Compared with pts who were not tested, gBRCAm-tested pts were younger at initial mBC diagnosis (median age: 53.5 vs. 62.0 years), had a shorter median disease-free interval before mBC diagnosis (821 vs. 959 days), and were less likely to have de novo mBC (28.0% vs. 31.2%). gBRCAm testing prevalence was 6.1% in the HR+ group (n=11,945) and 8.9% in the TNBC group (n=2430). gBRCAm testing rates mostly increased from 2014 to 2022 and were lowest in HR+ tumor subtypes; < 2/3 of all pts had a gBRCAm test from 2020 onwards (Table). Most pts with recurrent mBC (HR+: 68.3%; TNBC: 76.1%) were gBRCAm tested before diagnosis, whereas pts with de novo mBC were tested at a later timepoint ( > 60 days after mBC diagnosis – HR+: 48.3%; TNBC: 38.4%). Of all pts with gBRCAm diagnosed from 2018 onwards (n=187), 44.4% initiated PARPi. A higher proportion of pts with gBRCAm in the TNBC group initiated PARPi (52.9%) than in the HR+ group (42.4%). Pts with gBRCAm in the TNBC group received PARPi earlier than pts with gBRCAm in the HR+ group (mean days from mBC diagnosis to first PARPi use: 173 and 411 days, respectively). Fewer pts with de novo mBC (35.7%) initiated PARPi than pts with recurrent mBC (50.8%). With a median follow-up of 15.3 months, pts with gBRCAm initiated on PARPi had numerically longer median OS (32.3 months [95% CI: 24.2–47.4]) than PARPi non-initiators (21.4 months [95% CI:18.4–43.5]). OS results should be regarded with caution due to the small sample size (n=187). Conclusions: Despite NCCN guideline gBRCAm-testing recommendations, < 2/3 of pts with HER2-negative mBC in our study were gBRCAm tested from 2020 onwards. gBRCAm testing was lower in pts with HR+ disease and was performed at a later timepoint for pts with de novo disease. Wider and timelier implementation of gBRCAm testing to identify pts that could benefit from PARPi is warranted. Fewer pts with gBRCAm who had HR+ tumors or de novo disease received PARPi than pts with TNBC. Our data suggest that pts who initiated PARPi had numerically longer OS than PARPi non-initiators; further research into OS trends and PARPi use in gBRCAm mBC would be of interest. Editorial acknowledgment: Medical writing assistance was provided by Leigh-Ann Booth, Ph.D. from BOLDSCIENCE Inc., funded by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, US Legal entity responsible for the study: AstraZeneca. Funding: This study was supported by AstraZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, US, who are codeveloping olaparib. Table. gBRCAm testing rates over time in pts with HER2-negative mBC HER2-negative mBC is defined as IHC 0, or 1-positive, or IHC2-positive/ISH-negative. *Olaparib approved in mBC; †Olaparib approved in eBC. eBC, early breast cancer; gBRCAm, germline breast cancer gene mutation; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer; pt, patient; TNBC, triple-negative breast cancer. Citation Format: Siddhartha Yadav, Sam Hillman, Linlin Luo, Weiyan Li, Jagadeswara Earla, Xiaoqing Xu. BRCA testing and PARP inhibitor utilization in real-world HER2-negative metastatic 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 PS04-02.

Abstract PO5-06-11: RPL27A promotes the growth and metastasis of triple negative breast cancer by regulating Ribosome biogenesis

Abstract Background: Ribosome is a complex structure in cells for protein synthesis. It has been considered always have a constant composition. Recent studies have revealed that the Ribosome composition of tumor cells is heterogeneous. The Ribosome protein composition, post-translational modification, rRNA modification, and rRNA variants can lead to the existence of specialized "onco-ribosomes" in tumor cells, which regulates the rate of translation and protein synthesis, and can affect the occurrence and development of tumors significantly. The abnormal expression of multiple Ribosome proteins in triple-negative breast cancer may be the target of its diagnosis and treatment, also, an independent factor in prognosis evaluation. Methods: To learn the expression levels of Ribosome biogenesis related genes in normal breast cells and abnormal breast cells with different pathological subtypes of breast cancer, the following studies have been done: 1. Bioinformatics analysis on TCGA database and single-cell sequencing data; 2. IHC detection on TNBC tissue and adjacent tissues; 3. Determine the expression level of RPL27A in TNBC cells, and analyze the correlation between the expression of RPL27A and clinical information of patients. To explore the effect of RPL27A on Ribosome biogenesis, protein synthesis and other signaling pathways through Proteomics and molecular biology experiments have been designed and tested. The effects of RPL27A on malignant biological behaviors such as proliferation, migration, infiltration, and clonal formation of TNBC cells were studied through cell biology experiments and mouse experiments. Results: The analysis of TCGA database and single-cell sequencing data showed that the RPL27A was significantly increased in TNBC group. Immunohistochemical experiments showed that RPL27A was highly expressed in TNBC tissue and was impressively positively correlated with tumor size, lymph node metastasis, and bone metastasis. There was significantly negatively correlated with overall survival (OS) and disease free survival (DFS). It can be an independent factor for evaluating the prognosis of TNBC. By knocking out RPL27A in TNBC cell line, label free proteomics analysis showed that Ribosome biogenesis, protein synthesis, cell cycle regulation and other signaling pathways were obviously down regulated. Cell biology experiments have implied that the high expression of RPL27A in TNBC promotes cell proliferation, enhances cell migration, infiltration, and cloning ability, leads to more malignant biological behavior of tumor cells. Further research demonstrates that the high expression of RPL27A in TNBC significantly activated the EIF3C signal, cause changes in the composition of Ribosome in TNBC cells, promoted the formation of "onco-ribosomes", and distinctly increased the rate of protein synthesis. The study of PDX mice and Organoid showed that the knock out of RPL27A significantly reduced the growth rate and transfer ability of TNBC. Conclusion: The obvious over expressing of RPL27A in TNBC, which can significantly promote the growth and metastasis of tumor cells by influencing the Ribosome biogenesis process. Citation Format: Weipeng Zhao, Jingyi Zhang, Ye Zhu, Xin Yang, Xichuan Li. RPL27A promotes the growth and metastasis of triple negative breast cancer by regulating Ribosome biogenesis [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 PO5-06-11.

Abstract PO4-15-04: Differential genomic profiling of progesterone receptor (PR) negative, estrogen receptor (ER) positive HER2-negative metastatic breast cancer (MBC) through circulating tumor DNA

Abstract Background: MBC is usually classified based on ER and HER2 status. Although the absence of PR expression is commonly associated with a poorer response to endocrine therapy (ET) and an unfavorable prognosis, data regarding the underlining molecular features that occur in this subgroup are still unclear. The aim of this study was to investigate genomic differences between ER/PRpos HER2neg (PRpos) and ERpos PR/HER2neg (PRneg) MBC through circulating tumor DNA (ctDNA) profiling in a large multicenter consortium. Methods: This retrospective study analyzed a cohort of 1089 patients at Weill Cornell Medicine, Northwestern University, Massachusetts General Hospital, and Washington University in St. Louis with HER2neg MBC and ctDNA testing by Guardant360. Oncogenic pathway status (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, and PI3K) was defined based on previous research (Sanchez-Vega et al. Cell, 2018). Associations across single nucleotide variations (SNVs), copy number variations (CNVs), pathway classification, and ER/PR status were tested by multinomial logistic regression and corrected for significant clinical characteristics (i.e., lines of treatment, metastatic sites). Prognosis was analyzed through Cox regression for overall survival (OS) defined from time of ctDNA collection. Results: Among the 1089 analyzed patients, PRpos was the most represented subtype (N:580, 53%), followed by PRneg (N:300, 28%) and Triple Negative (TNBC) (N:209, 19%). In the hormone receptor positive subgroup, bone (N:663, 75%), liver (N:323, 37%) and lymph nodes (N:314, 36%) were the main sites of distant involvement. The TNBC group was exposed to significantly fewer lines of therapy (RRR:0.37, P= 0.005 for ≥5 lines). As compared to PRneg, TNBC had less frequent and PRpos had more frequent bone involvement (RRR:0.44, P< 0.001 and RRR:1.80, P< 0.001, respectively) and less frequent liver involvement (RRR:0.64, P=0.019 and RRR:0.71, P=0.020, respectively for TNBC and PRpos). After multivariable analysis, a significant difference with respect to PRneg was observed in SNVs for the PI3K and P53 pathways for TNBC (RRR 0.49 P = 0.013 and RRR 4.06 P < 0.001, respectively) but not for PRpos. On a single gene level, a lower incidence in CDH1 SNVs (RRR 0.09 P = 0.036) and a higher incidence of ESR1 SNVs (RRR 0.09 P = 0.036) was present in PRpos compared to PRneg. TNBC, on the other hand, was characterized by a lower prevalence of KRAS SNVs (RRR 0.09 P = 0.036) and PIK3CA SNVs (RRR 0.25 P < 0.001) and a higher prevalence of TP53 SNVs (RRR 0.09 P < 0.001). No ESR1mutations were detected in TNBC. Median OS was 15 months (mo) for TNBC, 21 mo for PRneg and 31 mo for PRpos (P < 0.001). The differential prognostic impact of ctDNA features on OS was then analyzed across the PRpos and PRneg subpopulations. ESR1 SNVs was prognostic for both subgroups in univariable analysis (HR 2.19 P < 0.001 and HR 1.96 P = 0.001 for PRpos and PRneg, respectively). In multivariable analysis corrected for lines of therapy, ESR1 SNVs retained its significance only in the PRpos subgroup (HR 1.41 P = 0.021) together with NF1 SNVs (HR 2.04 P = 0.034). On the other hand, TP53 SNVs had a significant impact on OS in the PRneg subgroup (HR 2.02 P = 0.014). Conclusions: Our study confirmed the prognostic impact of PR status in ER positive, HER2 negative MBC. Moreover, it suggested a differential profile in terms of ctDNA-detectable genomic features and their impact on survival, including well-established markers such as ESR1 SNVs, with a potential relevance for disease subtyping and future algorithms for drug development trials. Citation Format: Lorenzo Gerratana, Andrew Davis, Arielle Medford, Carolina Reduzzi, Katherine Clifton, Emily Podany, Whitney Hensing, Marko Velimirovic, Ami N. Shah, Lorenzo Foffano, Laura Munoz Arcos, Eleonora Nicolò, Charles S. Dai, Jennifer Keenan, Amir Behdad, Seth Wander, William Gradishar, Cynthia Ma, Fabio Puglisi, Aditya Bardia, Massimo Cristofanilli. Differential genomic profiling of progesterone receptor (PR) negative, estrogen receptor (ER) positive HER2-negative metastatic breast cancer (MBC) through circulating tumor DNA [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 PO4-15-04.

Abstract A014: Cell-free DNA concentration as a biomarker of response and recurrence in HER-2 negative breast cancer receiving neoadjuvant chemotherapy

Abstract Purpose: Cell-free DNA (cfDNA) shed into the blood by dying cells and its subset—circulating tumor DNA (ctDNA) exclusively released by tumors—are promising non-invasive biomarkers for predicting treatment response and survival. We sought to determine the clinical significance of cfDNA concentration in comparison to that of circulating tumor DNA (ctDNA) in patients with high-risk HER2-negative breast cancer receiving neoadjuvant chemotherapy (NAC) in the I-SPY2 trial. Methods: 283 patients with early-stage breast cancer (145 hormone receptor (HR)-positive/HER2-negative and 138 triple-negative) who had ctDNA data from a previous study (Magbanua et al. Cancer Cell 2023) were included in the analysis. CfDNA concentration in plasma was measured at pretreatment, during, and after NAC before surgery. Associations of cfDNA concentration (as a continuous and dichotomous variable using the median as cutoff) with clinicopathologic variables, response, and survival were examined. In addition, ctDNA data from the same cohort using a personalized tumor-informed test was available for comparative analysis (Magbanua et al., Cancer Cell 2023). The response endpoint was residual cancer burden (RCB) after NAC. The survival endpoint was distant recurrence-free survival (DRFS). Results: There were no significant differences in cfDNA concentration between the HR-positive/HER2-negative and TNBC groups at any time point. In the TNBC group, but not in HR-positive/HER2-negative group, high pretreatment cfDNA concentration was significantly associated with larger tumors (clinical stage T3/T4, Wilcoxon p=0.023) and higher grade (grade 3, Fisher p=0.0134). TNBC patients with no residual cancer (RCB-0 or pathologic complete response) after NAC had significantly higher cfDNA concentration 3 weeks after treatment initiation than those with extensive residual cancer after NAC (RCB-III, Kruskal-Wallis adjusted p=0.034). In the HR-positive/HER2-negative group, cfDNA concentration did not associate with response to NAC, but survival analysis showed that high cfDNA shedders at pretreatment had a significantly worse DRFS than low shedders (hazard ratio 2.12, 95% confidence interval 1.05-4.60, p=0.037). However, in the TNBC group, the difference in survival between high vs. low cfDNA shedders at all time points was not statistically significant. In contrast, as previously reported, ctDNA at all time points was significantly correlated with metastatic recurrence and death in both HR-positive/HER2-negative and TNBC groups (Magbanua et al., Cancer Cell 2023). Conclusions: In TNBC, cfDNA concentration reflected tumor burden, aggressiveness, and early response to NAC. In the HR-positive/HER2-negative group, pretreatment cfDNA concentration was prognostic for DRFS. Overall, the predictive and prognostic value of cfDNA concentration was more limited than that of ctDNA. Thus, ctDNA should be the measurement of choice when planning clinical interventions. Citation Format: Mark Jesus M. Magbanua, Ziad Ahmed, Rosalyn W. Sayaman, Lamorna Brown-Swigart, Gillian L. Hirst, Christina Yau, Denise M. Wolf, Wen Li, Amy L. Delson, Jane Perlmutter, W. Fraser Symmans, Douglas Yee, Nola M. Hylton, Laura J. Esserman, Angela M. DeMichele, Hope S. Rugo, Laura J. van ’t Veer. Cell-free DNA concentration as a biomarker of response and recurrence in HER-2 negative breast cancer receiving neoadjuvant chemotherapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A014.

Identification of triple-negative breast cancer and androgen receptor expression based on histogram and texture analysis of dynamic contrast-enhanced MRI

BackgroundTriple-negative breast cancer (TNBC) is highly malignant and has a poor prognosis due to the lack of effective therapeutic targets. Androgen receptor (AR) has been investigated as a possible therapeutic target. This study quantitatively assessed intratumor heterogeneity by histogram analysis of pharmacokinetic parameters and texture analysis on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to discriminate TNBC from non-triple-negative breast cancer (non-TNBC) and to identify AR expression in TNBC.MethodsThis retrospective study included 99 patients with histopathologically proven breast cancer (TNBC: 36, non-TNBC: 63) who underwent breast DCE-MRI before surgery. The pharmacokinetic parameters of DCE-MRI (Ktrans, Kep and Ve) and their corresponding texture parameters were calculated. The independent t-test, or Mann-Whitney U-test was used to compare quantitative parameters between TNBC and non-TNBC groups, and AR-positive (AR+) and AR-negative (AR-) TNBC groups. The parameters with significant difference between two groups were further involved in logistic regression analysis to build a prediction model for TNBC. The ROC analysis was conducted on each independent parameter and the TNBC predicting model for evaluating the discrimination performance. The area under the ROC curve (AUC), sensitivity and specificity were derived.ResultsThe binary logistic regression analysis revealed that Kep_Range (p = 0.032) and Ve_SumVariance (p = 0.005) were significantly higher in TNBC than in non-TNBC. The AUC of the combined model for identifying TNBC was 0.735 (p < 0.001) with a cut-off value of 0.268, and its sensitivity and specificity were 88.89% and 52.38%, respectively. The value of Kep_Compactness2 (p = 0.049), Kep_SphericalDisproportion (p = 0.049), and Ve_GlcmEntropy (p = 0.008) were higher in AR + TNBC group than in AR-TNBC group.ConclusionHistogram and texture analysis of breast lesions on DCE-MRI showed potential to identify TNBC, and the specific features can be possible predictors of AR expression, enhancing the ability to individualize the treatment of patients with TNBC.

Application of advanced diffusion models from diffusion weighted imaging in a large cohort study of breast lesions

BackgroundTo evaluate multiple parameters in multiple b-value diffusion-weighted imaging (DWI) in characterizing breast lesions and predicting prognostic factors and molecular subtypes.MethodsIn total, 504 patients who underwent 3-T magnetic resonance imaging (MRI) with T1-weighted dynamic contrast-enhanced (DCE) sequences, T2-weighted sequences and multiple b-value (7 values, from 0 to 3000 s/mm2) DWI were recruited. The average values of 13 parameters in 6 models were calculated and recorded. The pathological diagnosis of breast lesions was based on the latest World Health Organization (WHO) classification.ResultsTwelve parameters exhibited statistical significance in differentiating benign and malignant lesions. alpha demonstrated the highest sensitivity (89.5%), while sigma demonstrated the highest specificity (77.7%). The stretched-exponential model (SEM) demonstrated the highest sensitivity (90.8%), while the biexponential model demonstrated the highest specificity (80.8%). The highest AUC (0.882, 95% CI, 0.852–0.912) was achieved when all 13 parameters were combined. Prognostic factors were correlated with different parameters, but the correlation was relatively weak. Among the 6 parameters with significant differences among molecular subtypes of breast cancer, the Luminal A group and Luminal B (HER2 negative) group had relatively low values, and the HER2-enriched group and TNBC group had relatively high values.ConclusionsAll 13 parameters, independent or combined, provide valuable information in distinguishing malignant from benign breast lesions. These new parameters have limited meaning for predicting prognostic factors and molecular subtypes of malignant breast tumors.

Abstract 6124: Recombinant apurinic/apyrimidinic endonuclease-1/redox factor-1 plus acetylsalicylic acid combination therapy inhibits tumorigenesis in an orthotopic xenograft murine model of triple-negative breast cancer

Abstract Triple-negative breast cancer (TNBC) is characterized with hormone receptor negative and frequently exhibits inherently aggressive clinical behavior, resulting in poor prognoses. TNBCs are highly heterogenic, leading to obstacles in identifying new therapeutic targets and performing targeted therapy. Apurinic/apyrimidinic endonuclease 1/redox factor-1 (APE1/Ref-1), a multifunctional protein, is mainly involved in DNA repair and redox regulation; it is upregulated in various cancers and is extracellularly secreted because of hyperacetylation. We previously reported that hyperacetylation induced APE1/Ref-1 release causes apoptosis in TNBCs. In the current study, we aimed to assess the therapeutic efficacy of combination treatment involving recombinant human APE1/Ref-1 (rhAPE1/Ref-1) plus acetylsalicylic acid (ASA) in TNBC xenograft mice. ASA co-treatment was used to induce and lasting acetylation of rhAPE1/Ref-1. For in vivo analysis, we constructed an orthotopic xenograft in vivo model of TNBC by using MDA-MB-231 cells. We performed combination therapy involving intravenous injection of purified rhAPE1/Ref-1 (1 mg/kg) and oral administration of ASA (20 mg/kg) thrice a week for 6 weeks in TNBC xenograft mice. This rhAPE1/Ref-1 plus ASA combination therapy inhibited tumor formation and growth, without damaging liver or kidney tissue, and decreased plasma levels of the cancer marker CEA and breast cancer-specific markers CA27-29 and CA15-3 in the TNBC xenograft mice. The TNBC group, which underwent combination therapy, had more apoptotic cells and greater inflammatory cell infiltration in tumor tissues than the vehicle group did. Additionally, in tumor tissue of TNBC with combination therapy exhibits increased apoptosis following upregulation of Bax, cleaved-caspase-3, and cleaved-PARP. Thus, we found that rhAPE1/Ref-1 plus ASA combination therapy enhanced antitumor effects in TNBCs via inflammatory cell infiltration and apoptosis signaling pathways. Our findings indicate the therapeutic potential of rhAPE1/Ref-1 plus ASA combination therapy for TNBC. Citation Format: Yu Ran Lee, Hee Kyoung Joo, Eun-Ok Lee, Sungmin Kim, Hao Jin, Yeon Hee Choi, Eun Ju Choi, Byeong Hwa Jeon. Recombinant apurinic/apyrimidinic endonuclease-1/redox factor-1 plus acetylsalicylic acid combination therapy inhibits tumorigenesis in an orthotopic xenograft murine model of triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6124.

Abstract OT3-20-03: Refusal of Breast Surgery in Breast Cancer Patients With cCR After Neoadjuvant Systemic Therapy and Vacuum-assisted Biopsy (VAB) and SLNB Confirmed pCR. An interim report of the prospective non-randomized trial. NCT04293796

Abstract Introduction The aim of the study was to prove efficacy and safety of de-escalation of traditional breast surgery in BC patients who develop cCR after neoadjuvant systemic therapy. Refusal of surgery was offered to exceptional responders after vacuum-assisted tumor bed biopsy and sentinel lymph node biopsy confirmed absence of residual disease (pCR). Materials and methods A single-center prospective study was run in the NMRC n.a. N.N. Petrov. Starting from August of 2020, 35 patients with early сT1-2N0-1M0 (stage Ia-IIb) triple-negative and HER2-positive (both ER+ and ER-) unifocal tumours without DCIS in core-biopsy specimen enrolled in the study. Primary lesions were marked with a single clip in the centre. In cases with nodal involvement (cN1) the affected lymph nodes were also clipped. Patients with triple-negative breast cancer received 4 cycles of AC q21d followed by 12 cycles of weekly paclitaxel and carboplatin AUC 2.0. HER2-positive patients received 4 cycles of AC followed by 4 cycles of docetaxel combined with trastuzumab and pertuzumab q21d. Breast US, mammography and SPECT were used at baseline and at response evaluation. Vacuum-assisted biopsy was performed with 7G needle and US-guidance in the OR simultaneously with the SLNB. VAB protocol included retrieval of the tumor clip as first stage. Subsequently surrounding tissues were sampled, and markers were placed to guide radiotherapy. In case residual tumor was found patients received standard breast-conserving surgery. In case the sentinel lymph nodes were found to be positive, standard level II axillary clearance was performed. HER2-positive patients with pCR confirmed by VAB and SLNB received adjuvant trastuzumab up to one year. HER2-positive patients with residual breast or nodal involvement received trastuzumab emtansine up to one year. In case ER+, all patients received appropriate endocrine-therapy. In case of residual in-breast or nodal involvement patients with triple-negative breast cancer received standart capecitabine. Results The interim analysis included 25 patients in both groups. The median follow-up of disease-free survival for patients is 12 months. In the triple-negative group 12 patients achieved cCR. All patients went on to receive VAB and SLNB. After VAB and SLNB pCR was confirmed 11 patients (91.7%). 1 patient had invasive residual tumor with less than 5% cellularity. FNR in this group was 8.3% (1/12). Patient with invasive residual tumor received standard breast-conserving surgery. All the patients in the TNBC group were also found to be (sn)ypN0. In the HER2-positive group cCR was achieved 13 patients. All patients went on to receive VAB and SLNB. After VAB and SLNB pCR was confirmed 10 patients (77%). 3 patients had invasive residual tumor with less than 5% cellularity. FNR in this group was 23% (3/13). Patients with invasive residual tumor received standard breast-conserving surgery. All HER2-positive patients were found to be (sn)ypN0. One patient with HER2-positive subtype experienced a local reccurence in the postoperative zone 16 months after surgery. Initially, this patient achieved cCR and undergone VAB with SLNB. On final pathomorphologic examination isolated focuses of DCIS were found (ypTisN0). Standard breast-conserving surgery was performed and histologically only DCIS was found. This patient recieved 1-year of Trastuzumab and standard radiotherapy with boost. After the histologic confirmation of local reccurence patient underwent nipple-sparring mastectomy with reconstruction and nowadays she is recieveing therapy with trastuzumab emtansine (T-DM1). Conclusion All visualization modalities fail to provide reliable information on the true rate of pCR. Contemporary systemic therapy regimens after accurate selection of patients, following the inclusion criteria, allows to achieve pCR in 75-90%, thereby reducing the risk of FNR after VAB. The trial continues to enroll patients and further follow-up is needed. Citation Format: Petr Krivorotko, Sergey Yerechshenko, Alexander Emelyanov, Ekaterina Busko, Tengiz Tabagua, Viktoria Mortada, Konstantin Zernov, Alexander Komyakhov, Kirill Nikolaev, Elena Zhiltsova, Larisa Gigolaeva, Roman Pesotsky, Diana Enaldieva, Yana Bondarchuk, Nikolay Amirov, Valentin Channov, Sergey Novikov, Zhanna Bryantseva, Anna Artemyeva, Viktoriya Smirnova, Tatiana Semiglazova, Alexey Belyaev, Vladimir Semiglazov. Refusal of Breast Surgery in Breast Cancer Patients With cCR After Neoadjuvant Systemic Therapy and Vacuum-assisted Biopsy (VAB) and SLNB Confirmed pCR. An interim report of the prospective non-randomized trial. NCT04293796. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT3-20-03.

Identification of Altered Transcripts and Pathways in Triple Negative Breast Cancer

Abstract Triple negative breast cancer (TNBC) is a breast cancer subtype characterised by lack of oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor, and by worse prognosis than other cancer types. The aim of this study was to identify hub genes and molecular pathways for possible prognostic markers for TNBC. Nineteen breast cancer transcriptomes were sequenced using Illumina platform and analysed to identify differentially expressed genes in the TNBC subtype. Gene ontology enrichment analysis was conducted using the ToppGene tool. Then, the STRING online database was used for protein-protein interaction (PPI) network construction. Cytohubba and the MCODE plug-in were used to screen functional modules and hub genes. In total, 229 DEGs were identified by differential gene expression analysis in the TNBC group. Eight genes were screened out from the PPI network — FOXA1, ESR1, TFF1, GATA3, TFF3, AR, SLC39A6, COL9A1. In conclusion, this study indicates that the molecular subtype specific gene expression pattern provides useful information for targeted, biomarker-driven treatment options.

Expression of HIF-1α and markers of angiogenesis and metabolic adaptation in molecular subtypes of breast cancer

Hypoxic zones exist in solid tumors, where oxygen levels are significantly lower than in normal tissues. Hypoxia makes chemo-radiation therapeutics less effective and renders the metastatic potential more favorable. Emerging research has found that the transcriptional expression of hypoxia-inducible factor-1alpha (HIF-1α) promotes the transcription of vascular endothelial growth factor A (VEGF-A) and Hexokinase-I (HK-I), which are associated to cellular growth, angiogenesis, and metastatic invasion in many malignancies. However, it is still unclear whether VEGFA and HK-I expression has any influence on survival based on the intrinsic subtypes of breast cancer. Their prognostic significance remains a debatable topic. In the present study, quantitative Real-time polymerase chain reaction (qRT-PCR) was employed to check the relative expression of HIF-1α, VEGF-A and HK-I. The hazard ratios (HR) of breast cancer-specific and overall mortality were calculated using Cox proportional hazards model, which were adjusted for demographic, clinicopathological, and associated molecular variables, as well as the diagnosis year. The relative mRNA expression levels of HIF-1α (p = 0.0010) and VEGFA (p = 0.0119) were significantly higher in tumor tissues. The expression of both HIF-1α (p = 0.0111) and VEGFA (p = 0.0078) was higher in the TNBC group of breast cancers, while HK-I (p = 0.0106) was higher in ER/PR-positive, HER2-negative group. HIF-1α and HK-I overexpression were associated with a higher likelihood of survival, while overexpression of VEGFA was associated with a low survival rate, although it was not statistically significant.

Prediction of Clinical Molecular Typing of Breast Invasive Ductal Carcinoma Using 18F-FDG PET/CT Dual-Phase Imaging

To investigate the diagnostic value of Fluorine-18-labeled 2-fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (18F-FDG PET/CT) dual-phase imaging for the different molecular subtypes of invasive ductal carcinoma of the breast. Clinical imaging data of 164 women with invasive ductal carcinoma of the breast confirmed by pathology who underwent 18F-FDG PET/CT dual-phase imaging were retrospectively analyzed. The maximum standard uptake values (SUVmax) of the early and delayed phases of the lesion were measured and recorded as SUVmax1 and SUVmax2, respectively, and the retention index (RI) was calculated. We analyzed the change rule of SUVmax1, SUVmax2, and RI for the different molecular subtypes and molecular marker expression groups. The diagnostic threshold of different molecular marker expression status was determined using receiver operating characteristic curve analysis. SUVmax1 and SUVmax2 were highest in the TNBC group and lowest in the luminal A group (p<0.001). TNBC and HER2 overexpression groups had higher RI than the luminal A and B groups (p<0.001), with no significant difference between the TNBC and HER2 overexpression groups or between the luminal A and B groups (p=0.640 and 0.345, respectively). The ER- and PR-negative groups had significantly higher SUVmax1, SUVmax2, and RI than the PR-positive group (p<0.001). The HER2-positive group had higher SUVmax1 and SUVmax2 than the negative group (p<0.001). The Ki67 overexpression group had higher SUVmax1 and SUVmax2 levels than the low expression group (p<0.001). There was no significant difference in RI between HER2-positive and negative groups or between Ki67 high and low expression groups (p=0.904 and 0.216, respectively). For ER-negative and positive expression status, the maximum area under the curve (AUC) of SUVmax2 was 0.852, diagnostic threshold was 10.87, sensitivity was 79.6%, and specificity was 74.5%. For PR-negative and positive expression status, the AUC of SUVmax2 was 0.858, diagnostic threshold was 10.45, sensitivity was 83.1%, and specificity was 75.3%. For HER2-negative and positive expression status, the AUC of SUVmax1 was 0.714, diagnostic threshold was 9.28, sensitivity was 79.6%, and specificity was 60.9%. For Ki67 high- and low expression status, the AUC of SUVmax2 was 0.915 at maximum, diagnostic threshold was 10.21, sensitivity was 83.4%, and specificity was 93.9%. 18F-FDG PET/CT dual-phase imaging facilitates the prediction of the expression of molecular markers and subtypes of invasive ductal carcinoma of the breast and the development of more tailored treatment plans for patients with this disease.

Triple Negative Breast Cancer: Tumour Biology and Optimisation of Clinical Outcome

Triple negative breast cancer are breast cancer types that are difficult to treat because they lack expression of the estrogen receptor (ER), progesterone receptor (PR) and Human Epidermal Receptor 2 (HER2) gene amplification. Intensive research, analysis by the Cancer Genome Atlas (TCGA) Research Network and the advent of high-throughput technology tools has expanded the classification of TNBC tumors into subgroups according to its gene expression profiles in order to identify the different molecular subtypes, novel TNBC biomarkers that can play both predictive and prognostic roles and enhance therapeutic strategies. The “immune-activated,” subtype or tumours with defective BRCA pathway are amongst initial TNBC group with established genetic vulnerabilities that has allowed the addition of promising therapeutic approaches, including DNA-damaging agents (PARP inhibitors, platinum) as well as immunotherapy. The treatment of metastatic NBC (mTNBC) is currently transforming rapidly with better outcomes observed in clinical trials. The recent success with immune checkpoint inhibitors (ICIs) targeting the programmed cell death receptor 1 and programmed death ligand 1 (PD-L1) and PARP inhibitors for germline BRCA mutation-associated breast cancers as well as other novel strategies in mTNBC treatment will change the course of this unique cancer subtype in the future.

Mammographic and ultrasonographic features of triple-negative breast cancer compared with non-triple-negative breast cancer.

To evaluate and compare the mammographic and ultrasonographic features of TNBC with non-TNBC. A retrospective review of 193 invasive breast cancer patients (TNBC = 32 and non-TNBC = 161) was collected from January 2014 to June 2019. The imaging features were reviewed according to the 5th edition of the American College of Radiology Breast Imaging Reporting and Data System lexicon. We used the student t-test, Mann-Whitney U test, and Fisher's exact test for statistical analyses. Mass without calcifications was the most mammographic feature of TNBC (22 of 32, 68.8%) and more commonly found in TNBC than in non-TNBC (p = 0.007). The irregular shape (19 of 28, 67.9%) and indistinct margin (10 of 28, 35.7%) were the most common findings in the TNBC group. However, TNBC lesions appeared as round or oval shape and microlobulated margin more frequently than non-TNBC lesions (p < 0.001). Additionally, the tumor size and histological grade of TNBC were significantly higher than non-TNBC (p < 0.001). TNBC has distinct imaging features compared to non-TNBC. The imaging features on mammography combined with ultrasonography can be used to detect and differentiate this subtype from other breast cancers.

Dual function miR-205 is positively associated with ER and negatively with five-year survival in breast cancer patients

BackgroundPrecise molecular characterization of breast cancer, especially triple negative (TNBC) as the most lethal subtype, is needed to stratify patients for the individual treatment approach. MicroRNA-205 (miR-205) has tumor-suppressive and oncogenic functions across different cancers. Therefore, miR-205 might have a different role in TNBC and estrogen receptor (ER) positive BC. Our aim was to investigate how miR-205 expression is associated with ER/progesteron receptor status, clinical parameters, pathohistological characteristics of BC, and survival of patients MethodsWe determined miR-205 relative expressions in 73 primary breast tumors (50 TNBC and 23 ER+) by quantitative Real-time polymerase chain reaction (qPCR) and compared it to clinicopathological characteristics and outcome. ResultsThe highest levels of miR-205 were in the ER+ /PR+ group, and the lowest in the TNBC group (p = 0.009). Significantly higher levels of miR-205 were also observed in the ER+ compared with the ER-negative group, regardless of the PR status (p = 0.002). Low miR-205 expression level was associated with prognostic stage III in TNBC samples (p = 0.049). Patients who received adjuvant chemotherapy had significantly lower levels of miR-205 (p = 0.016). Patients who received hormone therapy had significantly higher levels of miR-205 (p = 0.007). The low-miR-205 patients had significantly higher 5-year survival rates (p = 0.041). ConclusionThe expression of miR-205 in BC is subtype-specific and high expression is associated with the ER+ tumors. The miR-205 expression might be a useful marker of TNBC progression. High miR-205 expression had a detrimental effect on BC patient outcome. Our results indicate that miR-205 might be utilized in clinical practice as a biomarker and an adjunct parameter for the selection of the most effective therapeutic modality.

A phase IB/II study of nivolumab in combination with eribulin in HER2-negative metastatic breast cancer (KCSG BR18-16).

1098 Background: Combining immune checkpoint inhibitors with chemotherapy has become a promising therapeutic strategy in metastatic breast cancer. Eribulin is a potent microtubule inhibitor and modulates the immune microenvironment of tumor cells. Therefore, combining eribulin to nivolumab may synergize antitumor efficacy in metastatic breast cancer. Methods: Adult patients with histologically confirmed recurrent/metastatic HER2- breast cancer were enrolled prospectively from 10 academic hospitals in Korea (ClinicalTrials.gov Identifier: NCT04061863). Key eligibility criteria included prior treatment with taxanes and/or anthracyclines, ≥1 measurable disease, and ≤2 prior cytotoxic chemotherapies in the metastatic setting. Patients received nivolumab 200 mg intravenously (IV) on day 1 plus eribulin 1.4 mg/m2 IV on day 1 and 8 of every 3 weeks until disease progression or intolerable toxicity. The dose level was determined from safety profile of three patients in run-in phase. The primary endpoint was investigator-assessed progression-free survival (PFS) rate at 6 months. Secondary endpoints included investigator-assessed objective response rate (ORR) per RECIST v1.1, disease control rate (DCR), overall survival (OS), and toxicity profile of the combination treatment. The association between PD-L1 expression by SP142 Ab and efficacy was analyzed. Results: From August 2019 to June 2021, 90 patients (HR+HER2- 45 pts/TNBC 45 pts), with a median age of 51 (range 31–71), were enrolled in the study. With a median study follow-up time of 16.3 months, 68 (75.6%) patients experienced progressive disease. PFS rate at 6-months was 49.6% and 24.1% in patients with HR+HER2- and TNBC group, respectively. Median PFS was 5.6 months (95% CI: 4.3-6.8) and 3.0 months (95% CI: 1.3-4.7) for HR+HER2- and TNBC group, respectively. ORRs were 53.3% (CR:0, PR: 24) for HR+HER2- and 21.8% (CR1, PR: 12) for TNBC. Patients with PD-L1+ tumors (PD-L1 expression ≥ 1% on TC or IC) had similar ORR compared to PD-L1- tumors (ORR 50% vs. 53.8% in HR+HER2-, 30.8% vs. 29.0% in TNBC). The most common grade 3/4 adverse event was neutropenia (15/90, 16.7%), and the most common immune-related adverse events were grade 1/2 hypothyroidism (19/90, 21.1%) and grade 1/2 pruritus (16/90, 17.8%). Five patients had discontinued study treatment due to immune-related adverse events (3 pneumonitis, 1 hepatitis, 1 skin rash). Conclusions: In this parallel phase II clinical trial, the addition of nivolumab to eribulin showed promising efficacy and tolerable safety profile in previously treated HER2- MBC. Further survival and exploratory analyses to find predictive markers will be followed. Clinical trial information: NCT04061863. [Table: see text]

Expression of PD-L1 in Locally Advanced Breast Cancer and Its Impact on Neoadjuvant Chemotherapy Response.

Objectives:Programmed cell death-ligand 1 (PD-L1) is a new target in breast cancer (BC) and its impact on neoadjuvant chemotherapy (NACTH) response is still unclear. The aim of this study was to investigate the prevalence of PD-L1 in locally advanced invasive BC of different molecular subtypes and to elucidate its relation to tumor-infiltrating lymphocytes (TILs) density, established clinicopathological factors, pathological therapy response after neoadjuvant chemotherapy and patients’ outcome. Materials and Methods:One hundred and five cases of locally advanced invasive BC were enrolled in our study. Cases were classified into five molecular subtypes according to the Immuno-histochemical data. PD-L1 immunostaining was analyzed for all studied cases and its expression was correlated with TILs density, histopathologic parameters, BC molecular subtypes, Pathological therapy response, 7-years disease-free survival (DFS) and overall survival (OS). Results:PD-L1 was expressed in 32.4% of the studied locally advanced BC cases. It showed a significant correlation with old age group (p= 0.010), high tumor grade (p= 0.046) and high pretherapy TILs density (p= <0.001). PD-L1 expression was higher in HER2/neu-enriched group (45.5%) followed by TNBC (44.4%). There were no significant relations between PD-L1 expression and DFS, OS as well as pathological therapy response, although, it revealed more expression in cases with complete and marked therapy response. Conclusion: In spite our results fail to prove that PD-L1 is a bad prognostic biomarker in locally advanced BC, but they indicate PD-L1 could be a new target for the treatment of patients with high grade breast carcinoma and TNBC group.

Abstract P3-18-09: Refusal of breast surgery in breast cancer patients with clinical complete response (cCR) after neoadjuvant systemic therapy and vacuum-assisted biopsy (VAB) and sentinel lymph node biopsy (SLNB) confirmed pathological complete response (pCR). A first report of the prospective non-randomized trial results. NCT04293796

Abstract Introduction The aim of the study was to prove efficacy and safety of refusal of traditional breast surgery in BC patients who develop cCR after neoadjuvant chemotherapy. Refusal of surgery was offered to exceptional responders after vacuum-assisted tumor bed biopsy and sentinel lymph node biopsy confirmed absence of residual disease (pCR). Materials and methods A single-center prospective study was run in the NMRC n.a. N.N. Petrov. Starting from August of 2020 20 patients with early сT1-2N0-1M0 (stage Ia-IIb) triple-negative and HER2-positive (both ER+ and ER-) unifocal tumours without in situ component in core-biopsy specimen enrolled in the study. Primary lesions were marked with a single clip in the centre. In cases with nodal involvement (cN1) the affected lymph nodes were also clipped. Patients with triple-negative breast cancer received 4 cycles of AC q21d followed by 12 cycles of weekly paclitaxel and carboplatinum AUC 2.0. HER2-positive patients received 4 cycles of AC followed by 4 cycles of docetaxel combined with trastuzumab and pertuzumab q21d. Breast US, mammography and SPECT were used at baseline and at response evaluation. Vacuum-assisted biopsy was performed with 7G needle and US-guidance in the OR simultaneously with the SLNB under general anesthesia. VAB protocol included retrieval of the tumor clip as first stage. Subsequently surrounding tissues were sampled, and markers were placed to guide radiotherapy. In case residual tumor was found patients received standard breast-conserving surgery. In case the sentinel lymph nodes were found to be positive, standard level II axillary clearance was performed. HER2-positive patients with pCR confirmed by VAB and SLNB received adjuvant trastuzumab up to one year. HER2-positive patients with residual breast or nodal involvement received trastuzumab-emtanzine up to one year. In case ER-positive, all patients received appropriate endocrine-therapy. In case of residual in-breast or nodal involvement patients with triple-negative breast cancer received 6 cycles of capecitabine. Results cCR was achieved in 8 of 10 patients in the HER2-positive group. VAB and SLNB were performed in 7 cases and confirmed pCR in 5 patients. 2 had residual in-breast disease with &amp;lt;10% cellularity. One patient with cCR requested standard surgical approach that confirmed pCR. 2 patients failed to obtain cCR. Both received standard surgery. In one of the cases no residual disease was found, in another one - a residual in-breast tumor was found at section. All HER2-positive patients were found to be sn ypN0. In the triple-negative group cCR was achieved in 6 of 10 patients. 4 patients went on to receive VAB and SLNB. After VAB and SLNB pCR was confirmed in three of them. 1 patient had residual tumor with less than 5% cellularity. Two patients with cCR after NAT opted for standard surgery. In both cases pCR was confirmed. 4 patients with clinically detectable residual in-breast tumor received standard surgery. All turned out to have pCR. All the patients in the TNBC group were also found to be sn ypN0.ConclusionVisualization modalities fail to provide reliable information on the true rate of pCR. Contemporary systemic therapy regimens provide the rate of pCR up to 60-70%. In all cases of NAT tumor bed marking at baseline is an essential procedure to guide future interventions and confirm their success. Discrepancies between radiologic assessment and true rates of pCR are a substrate for further search for the techniques that would challenge the role of surgery in exceptional responders developing cCR. The trial continues to enrol patients. Citation Format: Petr Krivorotko, Sergey Yerechshenko, Alexander Emelyanov, Ekaterina Busko, Alexander Bessonov, Viktoriya Gukova, Alexander Komyahov, Elena Zhiltsova, Kirill Nikolaev, Tengiz Tabagua, Larisa Gigolaeva, Roman Pesotsky, Sergey Novikov, Zhanna Bryantseva, Anna Artemyeva, Viktoriya Smirnova, Vladimir Kushnarev, Alexey Belyaev, Tatiana Semiglazova, Vladimir Semiglazov. Refusal of breast surgery in breast cancer patients with clinical complete response (cCR) after neoadjuvant systemic therapy and vacuum-assisted biopsy (VAB) and sentinel lymph node biopsy (SLNB) confirmed pathological complete response (pCR). A first report of the prospective non-randomized trial results. NCT04293796 [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 P3-18-09.

Abstract P1-08-12: The status of homologous recombination deficiency is a potential biomarker for platinum-based chemotherapy in triple-negative breast cancer

Abstract BackgroundTriple-negative breast cancer (TNBC) is a subtype of breast cancer that is highly susceptible to recurrence and metastasis. The therapeutic drugs are limited due to the lack of effective biomarkers predicting the therapeutic efficacy and prognosis of disease. Previous studies have shown that platinum-containing regimens are effective for both early and advanced TNBC, therefore, it is particularly important to explore biomarkers for predicting the efficacy of platinum drugs and to screen the population sensitive to platinum drugs. Methods All patients with available tumor specimens from National Cancer Center in China were eligible for this prospective-retrospective study (n=189), including 149 patients with early TNBC (NCT01150513, CH-BC-007) and 40 patients with advanced TNBC (12-123/657, CH-BC-018) who are treated with or without platinum. The primary endpoint is disease-free survival (DFS) for early TNBC and progression free survival (PFS) for advanced TNBC. For HRD status and genomic signatures, indexed libraries were subjected to probe-based hybridization with a customized NGS panel targeting 733 cancer-related genes. 3DMed-HRD algorithm was evaluated based on loss of heterozygosity score (LOH), telomeric allelic imbalance score (TAI) and large-scale state transition score (LST) to characterize genomic instability using over 10,000 single-nucleotide polymorphisms distributed across human genome, adjusted by tumor ploidy and purity. HRD positive is defined by HRD score above the threshold (cut-off ≥30) and/or deleterious mutation in BRCA1/2. ResultsDeleterious BRCA1/2 mutations were detected in 21.2% (40/189) of TNBC patients and 48.1% (91/189) were defined as HRD positive. In advanced TNBC cohort, 21 patients received platinum-containing and 19 received platinum-free chemotherapy regimens for first-line chemotherapy. The progression-free survival (PFS) of the platinum-containing group was longer than that of the platinum-free group (median PFS 9.13 vs 2.97 months, HR 0.39, 95%CI, 0.19-0.81, P=0.011), and the PFS of patients with HRD positive was significantly longer than HRD negative patients (median PFS 13.6 vs 6.80 months, HR 0.38, 95%CI, 0.15-0.99, P=0.048) in platinum-containing group. Interestingly, HRD-positive patients have a significantly shorter PFS than HRD-negative in platinum-free group (median PFS 1.97 vs 4.52 months, HR 3.67, 95%CI, 1.20-11.22, P=0.023). For the HRD-positive patients, median PFS was significantly better in platinum-based group than platinum-free group (median PFS 13.6 vs 1.97 months, HR 0.12, 95%CI, 0.03-0.43, P=0.001). In early-stage TNBC cohort (n=149), 74 patients received platinum-containing and 75 received platinum-free chemotherapy regimens for adjuvant chemotherapy. In platinum-containing group, no statistically significant difference was found in DFS between HRD-positive and HRD-negative patients (P=0.118). High-risk TNBC group (Ki-67 ≥ 15%) analysis revealed that HRD-positive patients had a numerical better DFS than HRD-negative patients (HR 0.43, 95%CI, 0.12-1.50, P=0.180). Among patients with HRD-positive, patients in platinum-containing group had a tendency to benefit more than those in platinum-free group (HR 0.35, 95%CI, 0.11-1.10, P=0.062). Conclusions: We developed a novel algorithm to evaluate 3DMed-HRD status and highlights the potential utility of HRD in guiding chemotherapy for TNBC patients in this retrospective analysis. In comparison to platinum-free chemotherapy, the advanced TNBC HRD positive patients with advanced TNBC receiving platinum-based chemotherapy is a preferable regimen, and the HRD negative patients might be on the contrary. Prospective validation with larger sample size is needed. Citation Format: Yimeng Chen, Xue Wang, Feng Du, Jian Yue, Yiran Si, Lina Cui, Bei Zhang, Binghe Xu, Peng Yuan. The status of homologous recombination deficiency is a potential biomarker for platinum-based chemotherapy 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 P1-08-12.