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PURPOSE Triple-negative breast cancer (TNBC) is a heterogeneous disease with variable response to neoadjuvant therapy (NAT). Pathologic complete response (pCR) has become a prognostic marker for overall and disease-free survival. The aim of this study was to determine if dynamic contrast-enhanced (DCE)-MRI after 2 and/or 4 cycles of NAT can identify patients with a high likelihood of achieving pCR, triaging them to standard of care (SOC), or, when appropriate, to de-escalation trials. Conversely, we aimed to identify chemoresistant tumors that are unlikely to achieve pCR and may benefit from escalated targeted trials. METHOD AND MATERIALS 309 patients with stage I-III TNBC underwent DCE-MRI (temporal resolution: 9-12 sec) at baseline (BL), 2 cycles (C2), and 4 cycles (C4) of SOC doxorubicin/cyclophosphamide (AC) NAT as part of a prospective IRB-approved study (NCT02276443). Tumor volumes of the index lesion were calculated using 3 axis measurements during the early phase of the DCE-MRI (60s). Percent tumor volume reduction (TVR) between BL, C2, and C4 was calculated. Patients were randomly assigned to a training or a validation cohort in a 1:1 ratio. pCR was assessed at surgery after completion of SOC NAT. Correlation between pCR and TVR was evaluated using ROC analysis. RESULTS Of 309 TNBC patients, 136 (44%) achieved pCR. Following 2 cycles of NAT, TVR >80% was predictive of pCR (chemosensitivity), while TVR ≤ 55% was predictive of non-pCR (chemoresistance) with PPV 80%, NPV 89%, AUC 0.811 (0.73~0.893, p< 0.0001) in the training cohort, and PPV 82%, NPV 85%, AUC 0.815 (CI:0.736~0.894, p< 0.0001) in the validation cohort. Following 4 cycles of NAT, TVR >90% was predictive of pCR, while TVR ≤80% was predictive of non-pCR with PPV 80%, NPV 84%, AUC 0.827 (0.756~0.898, p< 0.0001) in the training cohort and with PPV 73%, NPV 82%, AUC 0.785 (CI:0.709~0.862, p< 0.001) in the validation cohort. Using this model, the pCR status was correctly classified in 50% of TNBC patients using C2 DCE-MRI in the training cohort, and 54% in the validation cohort. Only 8% were misclassified in the training cohort, and 10% in the validation cohort. Using C4 DCE-MRI, the pCR status of 61% and 57% of TNBC was correctly classified in the validation and the testing cohorts, respectively. 12% were misclassified in the validation cohort, and 21% in the testing cohort. CONCLUSION DCE-MRI after 2 and 4 cycles of AC-based NAT correctly predicted the pCR status of 54% and 57% of TNBC patients, respectively, as either excellent responders or nonresponders with high AUC 0.811 and 0.827. This may allow patients to be triaged to SOC NAT with option of de-escalation or early targeted therapies for non-responders. Citation Format: Mary S. Guirguis, Beatriz Adrada, Miral Patel, Frances Perez, Rosalind Candelaria, Wei Yang, Jia Sun, Rania M. Mohamed, Medine Boge, H. T. Carisa Le-Petross, Jessica Leung, Gary J. Whitman, Deanna L. Lane, Marion E. Scoggins, Tanya Moseley, Benjamin Musall, Jason White, Sanaz Pashapoor, Peng Wei, Jong Bum Son, Ken-Pin Hwang, Bikash Panthi, Mark Pagel, Lei Huo, Kelly K. Hunt, Elizabeth Ravenberg, Alastair M. Thompson, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Stacy Moulder, Clinton Yam, Jingfei Ma, Gaiane Rauch. DCE-MRI for early prediction of excellent response versus chemoresistance in triple negative breast cancer [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 P1-05-15.

High stromal tumor-infiltrating lymphocytes (sTILs) are associated with improved pathologic complete response (pCR) in triple-negative breast cancer (TNBC). We hypothesize that integrating high sTILs and additional clinicopathologic features associated with pCR could enhance our ability to predict the group of patients on whom treatment de-escalation strategies could be tested. In this prospective early-stage TNBC neoadjuvant chemotherapy study, pretreatment biopsies from 408 patients were evaluated for their clinical and demographic features, as well as biomarkers including sTILs, Ki-67, PD-L1 and androgen receptor. Multivariate logistic regression models were developed to generate a computed response score to predict pCR. The pCR rate for the entire cohort was 41%. Recursive partitioning analysis identified ≥20% as the optimal cutoff for sTILs to denote 35% (143/408) of patients as having high sTILs, with a pCR rate of 59%, and 65% (265/408) of patients as having low sTILs, with a pCR rate of 31%. High Ki-67 (cutoff > 35%) was identified as the only predictor of pCR in addition to sTILs in the training set. This finding was verified in the testing set, where the highest computed response score encompassing both high sTILa and high Ki-67 predicted a pCR rate of 65%. Integrating Ki67 and sTIL may refine the selection of early stage TNBC patients for neoadjuvant clinical trials evaluating de-escalation strategies.

PURPOSE Triple negative breast cancer (TNBC) is an aggressive and heterogeneous subtype of breast cancer. Pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) predicts better survival. Early prediction of the treatment response can potentially triage non-responding patients to alternative protocol treatments, spare them of the unneeded toxicity, and improve pCR. We evaluated the ability of radiomic textural analysis of intratumoral and peritumoral regions on the dynamic contrast enhanced (DCE) and diffusion-weighted imaging (DWI) MRI images obtained early during NAST to predict pCR. MATERIALS AND METHODS This IRB-approved prospective study (NCT02276443) included 182 patients with biopsy proven stage I-III TNBC who had multiparametric MRIs at baseline (BL), post 2 cycles (C2), and post 4 cycles (C4) of NAST before surgery. Tumors and peritumoral regions of 5 mm and 10 mm in thickness were segmented on the 2.5 minutes DCE subtraction images and on the b=800 DWI images. Ten histogram-based first order texture features including mean, minimum, maximum, standard deviation, kurtosis, skewness, 1st, 5th, 95th, and 99th percentile, and 300 radiomic Grey Level Co-occurrence matrix (GLCM) features along with their absolute and relative differences between the 3 imaging time points were extracted from the tumors and from the peritumoral regions with an in-house Matlab toolbox. Treatment response at surgery (pCR vs non-pCR) was documented. The samples were divided into training and testing datasets by a 2:1 ratio. Area under the receiver operating characteristics curve (AUC ROC) was calculated for univariate analysis in predicting pCR. Logistic regression with elastic net regularization was performed for texture feature selection. Parameter optimization was performed by using 5-fold cross-validation based on mean cross-validated AUC in the training set. RESULTS Of 182 TNBC patients, 88 (48%) had pCR and 94 (52%) did not achieve pCR. Eight multivariate models combining radiomic features from both DCE and DWI tumoral and peritumoral regions had AUC > 0.8 (0.807-0.831) with p-value < 0.001 in both training and testing sets. The highest AUC=0.831 was obtained from a model consisting of 15 radiomic features: tumor DWI (5 GLCM features) at C2, peritumoral region on DCE (skewness) at C2, tumor DCE (1st, 5th percentile) at C4, tumor DWI (3 GLCM features) at C4, peritumoral region DWI (1 GLCM feature) at C4, and the relative difference between C4/C2 on DCE (5th, 95th percentile and mean). CONCLUSION Multi-parametric MRI-based radiomics models from the tumor and the peritumoral regions showed high accuracy as potential early predictors of NAST response in TNBC patients. Citation Format: Rania M. Mohamed, Bikash Panthi, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Elizabeth Ravenberg, Alyson Clayborn, Mark Pagel, Huiqin Chen, Jia Sun, Peng Wei, Alastair M. Thompson, Stacy Moulder, Anil Korkut, Lei Huo, Kelly K. Hunt, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Jingfei Ma, Gaiane Rauch. Multi-Parametric MRI-Based Radiomics Models from Tumor and Peritumoral Regions as Potential Predictors of Treatment Response to Neoadjuvant Systemic Therapy in Triple Negative Breast Cancer Patients [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 P6-01-06.

Background and Purpose Triple negative breast cancer (TNBC) is a biologically aggressive tumor and a refractory subtype of breast cancer due to the lack of therapeutic targets, such as estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2. In this study, we investigated the accuracy of radiomic models based on the dynamic contrast enhanced (DCE) MRI images obtained after the completion of NAST as discriminators of treatment response in TNBC patients. Materials and Methods This IRB-approved prospective study (ARTEMIS trial, NCT02276443) included 181 patients with biopsy proven stage I-III TNBC who Had MRIs after completion of NAST and before surgery. Patients were classified as pathologic complete response (pCR) and non-pCR at the surgery. Tumors were segmented on the 2.5 minutes DCE subtraction images. Regions with necrosis or clip artifacts were excluded from the contour. If tumors were not visible, the tumor bed was contoured. Whole-tumor histogram-based first order texture features (p=10) including mean, minimum, maximum, Standard deviation, kurtosis, skewness, 1st, 5th, 95th, and 99th percentiles, and radiomic (p=300) Grey Level Co-occurrence matrix (GLCM) features were extracted with an in-house Matlab toolbox. The samples were split into training and testing data sets by a 2:1 ratio. For univariate analysis area under the receiver operating characteristics curve (AUC ROC) was performed for pCR status prediction. For texture feature selection logistic regression with elastic net regularization was performed. Parameter optimization was performed by using 5-fold cross-validation based on mean cross-validated AUC in the training set. A P-value less than 0.05 was considered statistically significant. Results Of the total 181 patients, 88 (49%) had pCR and 93 (51%) had non-pCR. Univariate analysis identified 7 statistically significant first order imaging features (Minimum, Maximum, Mean, 1st Percentile, 5th Percentile, 95th Percentile, and 99th Percentile) with AUC >= 0.7 (p< 0.001), in both training and testing data sets. Percentile 5 showed highest AUC = 0.78 (p< 0.001). Two multivariate models were statistically significant at cross-validation with AUC>=0.7. The first model combined 2 first order data (Percentile 1 and Percentile 5) with AUC = 0.73 (p< 0.001). The second model combined 8 first order features (Percentile 1, 5, 95, 99, Mean, Minimum, Maximum, and Skewness) and 24 GLCM features with AUC = 0.7 (p=0.003). Conclusion DCE-MRI radiomic features from tumor and tumor bed regions in TNBC may be helpful imaging biomarkers for predicting treatment response after NAST. Citation Format: Rania M. Mohamed, Bikash Panthi, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Huiqin Chen, Jia Sun, Peng Wei, Jennifer K. Litton, Vicente Valero, Clinton Yam, Mark Pagel, Jingfei Ma, Gaiane Rauch. A Pre-operative Dynamic Contrast Enhanced MRI-Based Radiomics Models as Predictors of Treatment Response after Neoadjuvant Systemic Therapy in Triple Negative Breast Cancer Patients [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 P6-01-35.

Background: In the metastatic setting, low HER2 expression is associated with clinical benefit from trastuzumab deruxtecan, a HER2-targeting antibody drug conjugates. However, little is known about the biological significance of low HER2 expression in patients with early stage triple-negative breast cancer (TNBC) receiving neoadjuvant therapy (NAT). Methods: Out of 595 patients with stage I-III TNBC enrolled on the prospective ARTEMIS trial (NCT02276443) from 2015-2021, we identified 367 patients with available HER2 immunohistochemistry (IHC) results on pre-NAT tumor tissue (HER2-zero: n=218; HER2-low [IHC 1+, 2+]: n=149). All patients were treated with anthracycline-based NAT. In cases where sufficient pre-NAT tumor tissue were available, additional IHC and/or RNAseq were performed. Differential gene expression (DGE) and pathway analysis were performed using DEseq2. Gene set enrichment analysis (GSEA) was performed using the Hallmark gene sets. Deconvolution analyses were performed using CIBERSORT. We controlled for multiple hypothesis using a false discovery rate (FDR) threshold with the Benjamini-Hochberg method, accepting as significant genes with at least a 2-fold change and < 5% FDR. Results: Table 1 summarizes baseline clinicopathological features of the 367 patients. Compared to HER2-zero tumors, HER2-low tumors were less likely of metaplastic histology (p=0.001), associated with lower Ki67 (p=0.017) and were more likely to be androgen receptor (AR)-positive (p=0.01). There were no significant differences in tumor-infiltrating lymphocytes (TILs) infiltration and PD-L1 expression between HER2-zero and HER2-low tumors. Among the 226 patients with sufficient pre-NAT tissue for RNAseq, DGE analyses demonstrated upregulation of genes involved in fatty acid metabolism (ACSM1) and steroid hormone metabolism (DHRS2, UGT2B28) in HER2-low tumors compared with HER2-zero tumors. Deconvolution analyses revealed no significant differences between predicted proportions of immune cell subpopulations between HER2-low and HER2-zero tumors. Although rates of pCR were not significantly different between patients with HER2-zero (46%) and HER2-low tumors (40%) (p=0.34), non-pCR in patients with HER2-low tumors was associated with increased expression of EREG, which encodes an EGFR ligand, while non-pCR in patients with HER2-zero tumors was associated with downregulation in genes involved in immune response pathways. GSEA further identified the Hallmark allograft rejection (FDR q=0.001), interferon gamma response (FDR q=0.002), and interferon alpha response pathways (FDR q=0.007) as the 3 most significantly downregulated pathways in HER2-zero tumors from patients experiencing a non-pCR relative to HER2-zero tumors from patients experiencing a pCR. Conclusion: In early stage TNBC, low HER2 expression is associated with increased AR expression and upregulation of genes associated with fatty acid and steroid hormone metabolism. Gene expression analyses suggest that drivers of resistance to NAT differ between HER2-low and HER2-zero tumors. Biological differences between HER2-zero and HER2-low tumors exist and may influence future personalized treatment for patients with early stage TNBC. Citation Format: Clinton Yam, Ziyi Li, Anil Korkut, Wencai Ma, Elisabeth Kong, Holly A. Hill, Hussein Abbas, Sausan Abouharb, Beatriz Adrada, Banu K. Arun, Carlos H. Barcenas, Ajit Bisen, Daniel Booser, Aman Buzdar, Rosalind Candelaria, Junjie Chen, Alyson Clayborn, Senthil Damodaran, Qingqing Ding, Haven Garber, Gabriel N. Hortobagyi, Kelly K. Hunt, Nuhad K. Ibrahim, Adaeze Iheme, Meghan S. Karuturi, Kimberly Koenig, Rachel M. Layman, Jangsoon Lee, Jennifer K. Litton, Melissa Mitchell, Giancarlo Moscol, Jason Mouabbi, Rashmi K. Murthy, Oluchi Oke, Paula Pohlmann, David Ramirez, Elizabeth Ravenberg, Sadia Saleem, Mediget Teshome, Vicente Valero, Jason White, Madison Williams, Wendy Woodward, Chasity Yajima, Naoto T. Ueno, Ken Chen, Gaiane Rauch, Lei Huo, Debu Tripathy. HER2-01 Clinical and Molecular Characteristics of HER2-low/zero Early Stage Triple-Negative Breast Cancer [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 HER2-01.

Background and Purpose Early prediction of neoadjuvant systemic therapy (NAST) response in triple negative breast cancer (TNBC) patients could potentially aid in the selection of alternative therapies and avoid unnecessary toxicity in patients unlikely to achieve pathologic complete response (pCR) with NAST. In this study, we investigated the radiomic features of the peritumoral and the tumoral regions from dynamic contrast enhanced (DCE) MRI acquired at different time points of NAST for early treatment response prediction in TNBC. Methods and Materials This study included 182 biopsy-confirmed stage I-III TNBC patients enrolled in an IRB approved prospective clinical trial (NCT02276433). All patients underwent DCE-MRI on a GE 3T MRI scanner at baseline (BL), after two (C2) and four (C4) cycles of doxorubicin/cyclophosphamide based chemotherapy and before surgery. The peritumoral and the tumoral regions were segmented manually by two fellowship-trained radiologists using early phase (2.5 min) DCE-MRI subtraction images. Ten first order radiomic features, 300 grey-level-co-occurrence matrix (GLCM) features along with their absolute and relative differences (C4/BL, C2/BL, C4/C2) between the 3 imaging time points were extracted from the peritumoral and the tumoral regions. Patients were randomly divided into training and testing sets in a 2:1 ratio. For univariate analysis, area under the receiver operating characteristics curve (AUC ROC) was measured to determine the features most predictive of pCR/non-pCR. Wilcoxon Rank Sum test was used to test the statistical significance of predictive performance. In multivariate analysis, radiomic models were established using logistic regression with elastic net regularization followed by 5-fold cross validation for performance assessment. Results Eighty-eight (48%) patients had pCR (59 training, 29 testing) and 94 (52%) patients had non-pCR (63 training, 31 testing). Twenty-five radiomic features (4 from peritumoral C4, 5 from tumoral C4, 4 from peritumoral C4/BL, 6 from tumoral C4/BL, 2 from peritumoral C4/C2 and 4 from tumoral C4/C2) were statistically significant with AUC ≥ 0.75 in both the training and the testing sets at the univariate analysis. The significant features at C4 had AUCs of 0.75-0.79 for the training set and 0.76-0.81 for the testing set. Changes measured between C4 and BL or C2 showed AUC of 0.76-0.84 in the training and 0.75-0.81 in the testing datasets. Eleven multivariate regression models comprised of radiomic features at BL, C2, C4 and their changes (C4/BL, C4/C2 and C2/BL) showed an AUC of 0.80-0.84 for cross validation and an AUC of 0.80-0.82 for independent testing. Conclusions Radiomic models using longitudinal DCE MRI parameters of peritumoral and tumoral regions during NAST have the potential to predict pCR in TNBC patients undergoing NAST. Citation Format: Bikash Panthi, Rania M. Mohamed, Beatriz Adrada, Rosalind Candelaria, Mary S. Guirguis, Wei Yang, Medine Boge, Miral Patel, Nabil Elshafeey, Sanaz Pashapoor, Zijian Zhou, Jong Bum Son, Ken-Pin Hwang, H. T. Carisa Le-Petross, Jessica Leung, Marion E. Scoggins, Gary J. Whitman, Zhan Xu, Deanna L. Lane, Tanya Moseley, Frances Perez, Jason White, Elizabeth Ravenberg, Alyson Clayborn, Mark Pagel, Huiqin Chen, Jia Sun, Peng Wei, Alastair M. Thompson, Stacy Moulder, Anil Korkut, Lei Huo, Kelly K. Hunt, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Clinton Yam, Jingfei Ma, Gaiane Rauch. Longitudinal DCE-MRI Radiomic Models for Early Prediction of Response to Neoadjuvant Systemic Therapy (NAST) in Triple Negative Breast Cancer (TNBC) Patients [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 P6-01-34.