Neoadjuvant Chemotherapy In Patients Research Articles

The analysis of transcriptomic signature of TNBC—searching for the potential RNA-based predictive biomarkers to determine the chemotherapy sensitivity

AbstractNeoadjuvant chemotherapy is the foundation treatment for triple-negative breast cancer (TNBC) and frequently results in pathological complete response (pCR). However, there are large differences in clinical response and survival after neoadjuvant chemotherapy of TNBC patients. The aim was to identify genes whose expression significantly associates with the efficacy of neoadjuvant chemotherapy in patients with TNBC. Transcriptomes of 46 formalin-fixed paraffin-embedded (FFPE) tumor samples from TNBC patients were analyzed by RNA-seq by comparing 26 TNBCs with pCR versus 20 TNBCs with pathological partial remission (pPR). Subsequently, we narrowed down the list of genes to those that strongly correlated with drug sensitivity of 63 breast cancer cell lines based on Dependency Map Consortium data re-analysis. Furthermore, the list of genes was limited to those presenting specific expression in breast tumor cells as revealed in three large published single-cell RNA-seq breast cancer datasets. Finally, we analyzed which of the selected genes were significantly associated with overall survival (OS) in TNBC TCGA dataset. A total of 105 genes were significantly differentially expressed in comparison between pPR versus pCR. As revealed by PLSR analysis in breast cancer cell lines, out of 105 deregulated genes, 42 were associated with sensitivity to docetaxel, doxorubicin, paclitaxel, and/or cyclophosphamide. We found that 24 out of 42 sensitivity-associated genes displayed intermediate or strong expression in breast malignant cells using single-cell RNAseq re-analysis. Finally, 10 out of 24 genes were significantly associated with overall survival in TNBC TCGA dataset. Our RNA-seq-based findings suggest that there might be transcriptomic signature consisted of 24 genes specifically expressed in tumor malignant cells for predicting neoadjuvant response in FFPE samples from TNBC patients prior to treatment initiation. Additionally, nine out of 24 genes were potential survival predictors in TNBC. This group of 24 genes should be further investigated for its potential to be translated into a predictive test(s).

Radiomics analysis for prediction of lymph node metastasis after neoadjuvant chemotherapy based on pretreatment MRI in patients with locally advanced cervical cancer

BackgroundThis study aims to develop and validate a pretreatment MRI-based radiomics model to predict lymph node metastasis (LNM) following neoadjuvant chemotherapy (NACT) in patients with locally advanced cervical cancer (LACC).MethodsPatients with LACC who underwent NACT from two centers between 2013 and 2022 were enrolled retrospectively. Based on the lymph node (LN) status determined in the pathology reports after radical hysterectomy, patients were categorized as LN positive or negative. The patients from center 1 were assigned as the training set while those from center 2 formed the validation set. Radiomics features were extracted from pretreatment sagittal T2-weighted imaging (Sag-T2WI), axial diffusion-weighted imaging (Ax-DWI), and the delayed phase of dynamic contrast-enhanced sagittal T1-weighted imaging (Sag-T1C) for each patient. The K-best and least absolute shrinkage and selection operator (LASSO) methods were employed to reduce dimensionality, and the radiomics features strongly associated with LNM were selected and used to construct three single-sequence models. Furthermore, clinical variables were incorporated through multivariate regression analysis and fused with the selected radiomics features to construct the clinical-radiomics combined model. The diagnostic performance of the models was assessed using receiver operating characteristic (ROC) curve analysis. The clinical utility of the models was evaluated by the area under the ROC curve (AUC) and decision curve analysis (DCA).ResultsA total of 282 patients were included, comprising 171 patients in the training set, and 111 patients in the validation set. Compared to the Sag-T2WI model (AUC, 95%CI, training set, 0.797, 0.722-0.782; validation set, 0.648, 0.521-0.776) and the Sag-T1C model (AUC, 95%CI, training set, 0.802, 0.723-0.882; validation set, 0.630, 0.505-0.756), the Ax-DWI model exhibited the highest diagnostic performance with AUCs of 0.855 (95%CI, 0.791-0.919) in training set, and 0.753 (95%CI, 0.638-0.867) in validation set, respectively. The combined model, integrating selected features from three sequences and FIGO stage, surpassed predictive ability compared to the single-sequence models, with AUC of 0.889 (95%CI, 0.833-0.945) and 0.859 (95%CI, 0.781-0.936) in the training and validation sets, respectively.ConclusionsThe pretreatment MRI-based radiomics model, integrating radiomics features from three sequences and clinical variables, exhibited superior performance in predicting LNM following NACT in patients with LACC.

Predicting response to neoadjuvant chemotherapy for colorectal liver metastasis using deep learning on prechemotherapy cross-sectional imaging.

Deep learning models (DLMs) are applied across domains of health sciences to generate meaningful predictions. DLMs make use of neural networks to generate predictions from discrete data inputs. This study employs DLM on prechemotherapy cross-sectional imaging to predict patients' response to neoadjuvant chemotherapy. Adult patients with colorectal liver metastasis who underwent surgery after neoadjuvant chemotherapy were included. A DLM was trained on computed tomography images using attention-based multiple-instance learning. A logistic regression model incorporating clinical parameters of the Fong clinical risk score was used for comparison. Both model performances were benchmarked against the Response Evaluation Criteria in Solid Tumors criteria. A receiver operating curve was created and resulting area under the curve (AUC) was determined. Ninety-five patients were included, with 33,619 images available for study inclusion. Ninety-five percent of patients underwent 5-fluorouracil-based chemotherapy with oxaliplatin and/or irinotecan. Sixty percent of the patients were categorized as chemotherapy responders (30% reduction in tumor diameter). The DLM had an AUC of 0.77. The AUC for the clinical model was 0.41. Image-based DLM for prediction of response to neoadjuvant chemotherapy in patients with colorectal cancer liver metastases was superior to a clinical-based model. These results demonstrate potential to identify nonresponders to chemotherapy and guide select patients toward earlier curative resection.

A reduction in tumor volume exceeding 65% predicts a good histological response to neoadjuvant chemotherapy in patients with Ewing sarcoma.

No consensus exists for tumor volume response criteria in patients with Ewing sarcoma. This study aimed to identify an optimal cutoff for predicting a good histological response by analyzing tumor volume changes and tumor necrosis after neoadjuvant chemotherapy. We performed a retrospective analysis of 184 Ewing sarcoma patients, analyzing tumor volume changes before and after neoadjuvant chemotherapy. Patients were divided into two groups based on histological response: good (tumor necrosis ≥ 95%) and poor (tumor necrosis < 95%) responders. The receiver operating characteristic (ROC) area under the curve (AUC) method was used to determine the optimal thresholds for predicting the histological response. Additionally, the prognostic value of this cutoff for relapse-free survival was assessed. Out of 184 patients, 83 (45%) had tumor necrosis ≥ 95%, while 101 (55%) had tumor necrosis < 95%. ROC analysis identified the optimal cutoff for a good histological response as over 65% tumor volume reduction (AUC = 0.69; p < 0.001). Patients with volume reduction of ≥ 65% had a higher likelihood of a good histological response than those with lesser reductions (p = 0.004; odds ratio = 2.61). Multivariable analysis indicated a correlation between poor histological response and reduced relapse-free survival (hazard ratio = 2.17; p = 0.01), while tumor volume reduction itself did not impact survival. We reported that a tumor volume reduction of ≥ 65% was able to predict a good histological response in Ewing sarcoma patients. We recommend preoperative tumor volume assessment to identify patients at greater risk for poor histological response who could benefit from more intensive chemotherapy protocols or additional radiotherapy.

Tumor-infiltrating lymphocytes as a predictor of axillary and primary tumor pathological response after neoadjuvant chemotherapy in patients with breast cancer: a retrospective cohort study.

Tumor-infiltrating lymphocytes (TILs) can predict complete pathological response (pCR) of tumor in the breast but not so well-defined in the axilla after neoadjuvant chemotherapy. Since axillary surgery is being increasingly de-escalated after NACT, we aimed to investigate the relationship between TILs and pCR in the axilla and breast, as well as survival amongst NACT patients. Clinicopathological data on patients who underwent NACT between 2013 and 2020 were retrospectively examined. Specifically, pre-TILs (before NACT), post-TILs (after NACT) and ΔTIL (changes in TILs) were assessed. Primary endpoint was pCR and secondary endpoints were breast cancer-free interval (BCFI) and overall survival (OS). Two hundred and twenty patients with nodal metastases were included. Overall axillary and breast pCR rates were 42.7% (94/220) and 39.1% (86/220), respectively, whereas the combined pCR rate was 32.7% (72/220). High pre-TILs (OR 2.03, 95% CI 1.02-4.05; p = 0.04) predicted axillary pCR whereas, high post-TILs (OR 0.33, 95% CI 0.14-0.76; p = 0.009) and increased ΔTILs (OR 0.25, 95% CI 0.08-0.79; p = 0.02) predicted non-axillary pCR. TILs were not a significant predictor for BCFI and OS. This study supports the potential use of pre-TILs to select initially node-positive patients for axillary surgical de-escalation after NACT.

Abstract PO5-26-01: Assessing the effect of multimodal therapy in massive fungating breast cancers without distant metastasis

Abstract Background: Massive fungating breast cancers (MFBCs), which comprise exudative, foul-smelling tumors, the size of a child’s head or involve extensive ulceration are classified as locally advanced breast cancers. The National Comprehensive Cancer Network guidelines recommend preoperative neoadjuvant chemotherapy in patients with locally advanced breast cancer without distant metastases. However, limited evidence is available regarding the successful treatment of fungating breast cancers. In clinical practice, many fungating breast cancer cases are treated as stage IV tumors. This study aimed to investigate whether multimodal therapy, including surgery for giant breast cancers, can improve survival rates and whether the survival rates are comparable to those of other stage III breast cancers. Subjects and methods: Out of 1480 cases of primary breast cancer diagnosed at our hospital between June 2012 and March 2020, 123 patients with clinical stages IIIA–IIIC were chosen for analysis. Furthermore, 29 of these patients with MFBC were selected. During multimodal therapy for selected patients with fungating breast cancer, difficulties were encountered in some patients with single-stage skin suturing and closure after standard neoadjuvant chemotherapy. These patients underwent surgery with an additional skin flap or skin grafting. Furthermore, radiation therapy was added as needed. We compared the survival rates of these patients with those of patients who received drug therapy only according to the therapeutic protocol for Stage IV. Survival rates of patients with MFBC and other stage III breast cancers were also compared. Statistical analyses were conducted using the Kaplan–Meier curve and the log-rank test. Results: Of the 29 patients with MFBC, 22 (75.9%) and seven (24.1%) were treated with multimodal and palliative therapies, respectively. The median age and follow-up period of the multimodal therapy group were 62 (range: 43–94) years and 67 (range, 32–131) months, respectively. The corresponding values for the palliative therapy group were 79 (range: 42–88) years and 31 (range: 2–96) months. All patients in the palliative treatment group were hormone receptor positive and HER2 negative, and treatment with hormone therapy was initiated. The 7-year survival rate was significantly higher in the multimodal therapy group than in the palliative treatment group (92.3% vs. 68.6%, p = 0.0317). Furthermore, the 5-year distant recurrence-free rate was higher in the multimodal treatment group (79.3% vs. 63.5%). Local recurrence did not occur in any patient in the multimodal treatment group. There was no significant difference in the 7-year survival rates between patients with MFBC and those with other stage III breast cancers (86.8% vs. 75.3%; p = 0.239). Triple-negative breast cancer accounted for 20.8% (20 96) of the other stage III breast cancers, but none of these were MFBCs. Conclusions: Clinically, MFBCs are often palliatively treated as stage IV tumors, even in the absence of distant metastasis. However, the survival rate was significantly higher in the multimodal therapy group than in the palliative treatment group. Furthermore, the survival and distant recurrence-free rates for MFBC were higher than those for other stage III breast cancers. Therefore, patients with MFBCs should be actively treated using curative treatments. Citation Format: Tamaki Tamanuki, Maki Namura, Tomoyoshi Aoyagi, Haruhito Sakata, Mika Iwai, Shinichirou Shimizu, Hiroshi Matsuzaki. Assessing the effect of multimodal therapy in massive fungating breast cancers without distant metastasis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-26-01.

Abstract PO4-03-05: Prognostic value of Ki67 expression in post-treatment tumors of patients with residual triple-negative breast cancer after neoadjuvant chemotherapy

Abstract Introduction Patients with triple-negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) against neoadjuvant chemotherapy (NAC) have a poor prognosis. The prognosis of these patients can be differentiated using various parameters, including the Residual Cancer Burden (RCB) index and tumor-infiltrating lymphocytes. In this study, we took a different angle and aimed to evaluate the prognostic value of post-treatment Ki67 expression, which was examined in tumors following NAC in patients with non-pCR TNBC. Methods A retrospective review of clinical records from February 2008 to December 2021 was conducted of patients from Gangnam Severance Hospital and Asan Medical Center, both in Seoul, South Korea. We included patients with non-metastatic TNBC who underwent NAC including anthracycline and taxane regimens, followed by curative surgery, regardless of adjuvant capecitabine receipt. Ki67 expression and the RCB index were evaluated using residual tumors obtained from surgery. High Ki67 expression was defined as ≥20%. The 5-year recurrence-free survival (RFS) was estimated using Kaplan-Meier analysis, and hazard ratios (HR) were calculated using Cox regression analysis. Results This study included 338 patients with available Ki67 expression data in residual tumors. Among them, 110 patients (30.9%) had low Ki67 expression, while 228 patients (64%) had high Ki67 expression. At a median follow-up of 34 months, those with low Ki67 expression had a 5-year RFS rate of 82.6%, while those with high Ki67 expression had a rate of 58.3%, with a HR of 0.345 (95% CI 0.210-0.565, p&amp;lt; 0.001). When stratified by the RCB index, the 5-year RFS of RCB-I patients was 93%, RCB-II patients 70.2%, and RCB-III patients 40.5%. When assessing survival outcomes based on both Ki67 expression and the RCB index, patients with RCB-I and low Ki67 (n=26) had a 100% 5-year RFS rate. Patients with RCB-I and high Ki67 (n=24) had a rate of 83.3%. Notably, in patients with RCB-III and high Ki67 (n=62), the 5-year RFS rate was 35.5% and there was no significant difference in RFS based on the receipt of adjuvant capecitabine (median RFS: capecitabine - 18 months, observation - 15 months, p-value=0.994). Conclusions Our findings demonstrate the prognostic value of Ki67 expression in residual TNBC after NAC, indicating that cases with low Ki67 expression have a favorable outcome. Combining Ki67 expression with the RCB index allows identification of patients with good residual disease (i.e. low Ki67 expression and RCB-I) who could be potential candidates for de-escalating adjuvant treatments such as capecitabine or pembrolizumab. However, for patients with high Ki67 expression and RCB-III, novel strategies are required to improve survival outcomes beyond the use of capecitabine. Citation Format: Yoonwon Kook, Soo-Young Lee, Seung Ho Baek, Min Ji Kim, Junghyun Kim, Sohyun Moon, Seung Eun Lee, Soong June Bae, Joon Jeong, Sae Byul Lee, Sung Gwe Ahn. Prognostic value of Ki67 expression in post-treatment tumors of patients with residual triple-negative breast cancer after neoadjuvant chemotherapy [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 PO4-03-05.

Abstract PO4-25-03: Comprehensive immune profiling reveals factors associated with neoadjuvant chemotherapy response in triple negative breast cancer

Abstract Background: KEYNOTE-522 has resulted in FDA approval of the immune checkpoint blocker pembrolizumab with neoadjuvant chemotherapy for patients with high-risk triple negative breast cancer (TNBC), given the remarkable improvement in pCR rate to 65% along with improvement in event free survival, while with chemotherapy alone, the pCR rate is 40-50%. Unfortunately, use of pembrolizumab is associated with several immune related adverse events (irAE), some of which can be life-threatening and debilitating, including cardiomyositis, encephalitis, and adrenal insufficiency, among others. Hence, there is an unmet need to identify biomarkers in the tumor microenvironment which could predict patients who may attain pCR with chemotherapy alone and be spared the side effects from the added PD-1 inhibition. Methods: Comprehensive immune profiling, including PD-L1 IHC and the expression of 395 immune genes by RNA-seq, was performed on 1:2 matched FFPE tumor samples from 23 stage 1-3 TNBC patients (2 stage 1, 6 stage 2, 15 stage 3). All patients were female with an average age of 48 years (range: 25-79 years). 14 patients were treated with neoadjuvant chemotherapy alone (NAC) and 9 were treated with neoadjuvant chemotherapy combined with the checkpoint inhibitor pembrolizumab (NAC+I). mRNA expression signatures of tumor inflammation (TIGS, weak/moderate/strong), cell proliferation (CP, poor/moderate/high), and cancer testis antigen expression burden (CTAB) were determined by RNA-sequencing. Statistical comparisons of quantitative biomarkers between groups were calculated using the Wilcoxon Rank-Sum test, overrepresentation analysis of categorical variables between groups was calculated by proportions test, and survival differences were quantified by Cox proportional hazards analysis. Pathological responses were documented as pathological complete response (pCR) vs. non-pCR. Results: Across the entire cohort, patients with a BMI &amp;lt; 30 had significantly higher PD-L1 expression (assessed by RNA) than those with a BMI ³ 30 [p=0.047]. While not a statistically significant association, the NAC+I group tended to have a higher pCR rate compared to the NAC group [44.4% vs. 28.6%, p=0.66]. Across the entire cohort, tumors with high CTA expression, designated as CTAB high, had a higher pCR rate than CTAB low tumors [54.5% vs 16.7%, p=0.089]. No significant difference in pCR rate between TIGS or CP groups was detected for the NAC group, but in the NAC+I group, highly proliferative tumors had a lower pCR rate than moderately proliferative tumors [0% vs. 80%, p=0.048]. The pCR and non-pCR groups for each treatment type also exhibited distinct gene expression profiles. Among the NAC group, underexpression of FOXP3 and overexpression of MAPK14 and CD44 were associated with pCR [p≤0.031], while underexpression of IFNB1, MAPK14, and CD44 was associated with non-pCR [p≤0.029]. Among the NAC+I group, overexpression of CXCR4, TNFR and CCL20 was associated with non-pCR [p≤0.046]. Interestingly, SDHA was significantly overexpressed in the non-pCR subset of patients in the NAC group and significantly underexpressed in the non-pCR subset of patients in the NAC+I group [p≤0.031]. Conclusions: The development of biomarkers of treatment response is essential to the integration of immunotherapy with chemotherapy as a combined cancer treatment. Our study profiled the immune context of both NAC and NAC+I and identified several key microenvironmental differences underlying divergent treatment response in both groups. A comprehensive understanding of these factors could potentially predict pCR to chemotherapy alone, enabling the avoidance of the unnecessary treatment of these tumors with immunotherapy. Citation Format: Robert Seager, Heidi Ko, Sarabjot Pabla, Maria-Fernanda Senosain, Pawel Kalinski, Erik Van Roey, Shuang Gao, Kyle Strickland, Rebecca Previs, Mary Nesline, Stephanie Hastings, Shengle Zhang, Jeffrey Conroy, Taylor Jensen, Marcia Eisenberg, Brian Caveney, Eric Severson, Shakti Ramkissoon, Shipra Gandhi. Comprehensive immune profiling reveals factors associated with neoadjuvant chemotherapy response in triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-25-03.

Abstract PS14-02: Real-world analysis comparing Black and White patients with triple-negative breast cancer receiving therapy per KEYNOTE-522

Abstract Abstract Title: Real-world analysis comparing Black and White patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 Background: KEYNOTE-522 was a randomized, double-blind, placebo-controlled phase 3 trial which resulted in the FDA approval of pembrolizumab with neoadjuvant chemotherapy for patients with newly diagnosed, high-risk, early-stage triple-negative breast cancer (TNBC). Despite the significant improvement in pathological complete response (pCR) and event-free survival rates across all patients, the landmark trial included only 4.5% Black patients. It is essential to assess outcomes in representative treatment populations. We assessed real-world toxicity and treatment outcomes across Black and White patients who received standard-of-care treatment per KEYNOTE-522. Methods: In this retrospective, multicenter study, we examined patients with early-stage TNBC who received planned treatment per KEYNOTE-522 as standard-of-care (SOC) therapy. 16 sites were included in the analysis. IRB approval was obtained from each participating site. Number and length of treatment delays, treatment-related toxicities (both chemotherapy and immune-related) of all grades, and pCR rate were collected from the electronic medical record of each participating site, and deidentified data were shared for central analysis. Results: Of the 577 patients who initiated treatment with chemotherapy and immunotherapy, 534 patients were included in this analysis with 105 patients who self-identified as Black (19.7%) and 429 who self-identified as White (80.3%). There were no statistically significant differences in clinical and pathological characteristics between the two groups. White women were more likely to have grade 3+ immune-related adverse events (irAEs) compared to Black women (33.8% vs 20.9%, P=0.011). There was no significant difference across Black and White patients with respect to grade 3+ chemotherapy-related adverse events. Out of the 444 patients who have completed surgery, no difference in pCR rate was observed between Black and White women (45/86 52.3% vs 200/358 55.9%) (p = 0.6). The authors also saw no difference in the rates of hospitalizations between Black and White women (39% vs 36% p = 0.5), and rates of acute care utilization (38% vs 38% p = 0.9). Conclusions: We report safety and efficacy across Black and White women in a real-world analysis of patients who received treatment per KEYNOTE-522. Notably, White patients had a significantly higher frequency of grade 3+ irAEs, although the reason for this finding is unclear based on this analysis. Black patients had similar pCR rates and rates of treatment-related hospitalizations compared to White patients. Assessment of outcomes and toxicity by race in clinical trials and real-world analyses are critical in drug development. Citation Format: Mara Hofherr, Andrew Davis, Spenser January, Emily Owen, Farah Raheem, Lida A. Mina, Suganya Arunachalam Karikalan, Lauren Lyons, Meredith Watson Rose, Katherine Madden, Jerline Hsin, Aimee Keegan, Wai Yu, Shawna Kraft, Allison Schepers, Emily Armgardt, Douglas Mazewski, Alison Svoboda, Kayla Harwood, Jodi Taraba, Yonatan Resnick, Shelly Hummert, Lisa Grate, Sidney Keisner, Jacob Hobbs, Todd Davis, Kristin Bastian, Dawn Minikel, Wiliam Adler, Traci White, Avneek Singh Sandu, Fouad Boulbol, Kelsey Finch, Katherine Clifton. Real-world analysis comparing Black and White patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 [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 PS14-02.

Abstract RF02-07: Precocious modulation of metabolic and immunological parameters predicts tumor response to fasting-mimicking diet plus chemotherapy in patients with early stage TNBC

Abstract Background: Preclinical studies showed that severely calorie restricted fasting-mimicking diets (FMDs) enhance the antitumor efficacy of chemotherapy (CT) or immunotherapy (IO) in murine triple negative breast cancer (TNBC) models. These effects are mediated by a combination of blood glucose reduction and positive immunomodulatory effects. Moreover, combining fasting and metformin produced synergistic anticancer effects in a broad range of tumor models. The BREAKFAST trial was designed to investigate if FMD, plus/minus metformin, could increase the antitumor activity of neoadjuvant CT in patients with stage I-III TNBC. Methods: BREAKFAST (NCT04248998) is a randomized, non-comparative, phase II, pilot trial that enrolled stage I-III (cT&amp;gt;1 cm) TNBC patients (pts) candidate to receive 4 cycles of neoadjuvant CT with doxorubicin-cyclophosphamide every 3 weeks, followed by 12 cycles of weekly paclitaxel. Pts were randomized 1:1 to receive: CT plus 5-day FMD every 3 weeks, up to 8 cycles (arm A); CT plus FMD plus daily metformin (1700 mg) (arm B). The primary study endpoint was the rate of pCR in either experimental arm. Secondary/exploratory endpoints included safety, compliance, and biomarker analyses based on blood metabolomics and tumor transcriptomics analyses at different timepoints. Results: Between June 2020 and February 2022 we enrolled 30 pts. Then, the study was interrupted after the introduction of chemo-immunotherapy (CT-IO) as a standard neoadjuvant therapy for early stage TNBC pts. Among 30 pts, 13 were treated with CT plus FMD, while 17 pts received CT plus FMD plus metformin. Overall, pCR rate was 56.6%, i.e., significantly higher than pCR rates reported with anthracycline-taxane CT alone in previous phase II/III trials (26-39%), with no significant differences among treatment arms (p=0.49). The FMD acutely reduced blood glucose, insulin and LDH levels, which reflects a reduction in systemic and/or tumor glucose metabolism. Of note, precocious LDH reduction was more pronounced in patients undergoing pCR. RNA-seq analysis of tumor samples revealed a significant downmodulation of glycolysis and TCA cycle pathways after one treatment cycle, paralleled by an increase of intratumor activated T cells, memory T cells and NK cells, as estimated by deconvolution analyses of tumor transcriptomic data. Of note, these changes were observed only in patients achieving pCR. While intratumor metabolic changes were similar in the two treatment arms, the modulation of intratumor immunity was more pronounced in patients not receiving metformin. Conclusion: Preoperative CT plus cyclic FMD (plus/minus metformin) results in excellent pCR rates in localized TNBC patients. Early on-treatment downregulation of systemic and intratumor metabolic parameters related to glucose metabolism predicts pCR, and this is independent of metformin use. Based on results of this study, we recently initiated a large, multicentric trial, namely the BREAKFAST-2 (NCT05763992) study, which will investigate if adding cyclic FMD to neoadjuvant CT-IO increases pCR rates in ~ 145 pts with stage II-III TNBC. Citation Format: Francesca Ligorio, Giovanni Fucà, Andrea Vingiani, Fabio Iannelli, Riccardo Lobefaro, Leonardo Provenzano, Lucrezia Zanenga, Cristina Ferraris, Antonino Belfiore, Silvia Brich, Alessia Bertolotti, Gianfranco Scaperrotta, Catherine Depretto, Antonia Martinetti, Elisa Sottotetti, Paola Antonia Corsetto, Giulia Valeria Bianchi, Giuseppe Capri, Secondo Folli, Saverio Minucci, Marco Foiani, Massimiliano Pagani, Giancarlo Pruneri, Filippo De Braud, Claudio Vernieri. Precocious modulation of metabolic and immunological parameters predicts tumor response to fasting-mimicking diet plus chemotherapy in patients with early stage TNBC [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 RF02-07.

Abstract PS05-09: A single-arm Phase II clinical study of fulvestrant combined with chemotherapy in the neoadjuvant treatment of HR+/HER2- locally advanced breast cancer

Abstract Background: HR+/HER2- breast cancer has been found to be less sensitive to neoadjuvant chemotherapy (NCT), leading to an objective response rate (ORR) of approximately 65%. Endocrine therapy combined with chemotherapy may help improve the ORR in these patients. The objective of this Phase II study was to evaluate the efficacy and safety of adding fulvestrant to NCT in patients with HR+/HER2- locally advanced breast cancer(LABC). Additionally, the study aimed to investigate the association of 18F-FES PET/CT and metabolites with efficacy. Methods: In this single-arm Phase II study, eligible patients were females with histologically confirmed HR+/HER2- LABC (Stage IIB-IIIC). Patients received fulvestrant (500 mg, on days 0, 14, 28, then every 28 days thereafter, every 4 weeks for six cycles) plus AC-T regimen, followed by surgery. Premenopausal women were administered a concomitant GnRH analogue. Patients underwent 18F-FES PET/CT before the initiation of fulvestrant, and plasma samples were collected for LC-MS analysis at baseline. The primary endpoint was ORR. Secondary endpoints included pathological complete response (tpCR) and safety. Results: From December 2020 to September 2022, 36 patients were enrolled. The median age was 53 years (range35-67). 78% were ECOG PS of 1, 69% were postmenopausal, 92% were nodal involved, and 83% were in stage III. After neoadjuvant therapy, the ORR was 86.1%. All patients completed the surgery, with a tpCR rate of 8.3% (3/36). 80.6% (29/36) patients were classified as Miller-Payne (MP) grade ≥3. Grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 22% (8/36) of the participants. The most common TEAEs were neutropenia (13.9%) and leukopenia (8.3%). The expression of ER, PR, and Ki-67 in postoperative pathology significantly decreased compared to baseline (p &amp;lt; 0.05). Additionally, the change in ER expression was significantly correlated with the regression volume of primary breast tumors (R = 0.56, p = 0.0044). The decrease in ER value in patients with MP ≥ 4 was significantly larger than in patients with MP ≤ 3 (p = 0.0054). Among the 36 patients, 24 completed the 18F-FES PET/CT scan before initiating fulvestrant.The average SUVmax in primary breast lesions was 4.17 (range 1.00-12.80). The SUVmax of breast lesions was significantly correlated with clinical efficacy (p = 0.0018) and with changes in ER expression before and after treatment (R = 0.68, p = 0.00023). Meanwhile, the SUVmax of patients with MP ≥ 4 grade was significantly higher than that of patients with MP ≤ 3 grade (p=0.018). A total of 25 plasma samples were available for metabolic analysis. Among these samples, 13 differential metabolites were identified between patients with MP ≥ 4 grade and MP ≤ 3 grade, which were markedly enriched in 19 metabolic pathways. Conclusions: The addition of fulvestrant to NCT showed manageable toxicity and promising antitumor activity for patients with HR+/HER2- LABC. 18F-FES PET/CT might serve as a tool to predict the effectiveness of neoadjuvant combination therapy. Altered metabolites or metabolic pathways might be associated with the response to this combined treatment approach. Keywords: breast cancer, HR+/HER2-, fulvestrant, neoadjuvant treatment, 18F-FES PET/CT Citation Format: Qing Shao, Jing Wu, Ningning Zhang, Xiaohua Zeng. A single-arm Phase II clinical study of fulvestrant combined with chemotherapy in the neoadjuvant treatment of HR+/HER2- locally advanced breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS05-09.

Abstract PO4-03-06: Body mass index and response to neoadjuvant chemo-immunotherapy among women with primary triple negative breast cancer

Abstract Background: Elevated body mass index (BMI) is associated with lower rates of pathologic complete response (pCR) after neoadjuvant chemotherapy in patients with breast cancer. The addition of PD-1 receptor inhibition with pembrolizumab to neoadjuvant chemotherapy is now considered the standard of care for patients with stage II or III triple negative breast cancer (TNBC) based on results from the KEYNOTE-522 (KN-522) trial. In other cancer types such as melanoma and lung cancer, patients with overweight/obesity have better survival outcomes following treatment with immunotherapy compared to patients with normal weight, despite a higher incidence of any-grade immune-related adverse events (irAEs). Whether BMI is associated with differential response and toxicity in patients with TNBC treated with neoadjuvant chemo-immunotherapy is unknown. Methods: Patients with stage II-III TNBC treated with neoadjuvant chemotherapy plus pembrolizumab per the KN-522 regimen from 8/2021 – 9/2022 at Memorial Sloan Kettering Cancer Center were included in this retrospective study. Patient characteristics, tumor characteristics, treatments, surgical pathology information, and irAEs were abstracted from medical records. pCR was defined as absence of invasive or in situ carcinoma in breast and axillary node tissue surgical specimens. BMI was categorized per standard definitions: underweight/normal weight &amp;lt; 25 kg/m2, overweight 25-29.9 kg/m2, and obese &amp;gt;=30 kg/m2. Wilcoxon rank sum tests, Pearson’s chi-squared tests, and Kendall rank correlation tests were used to test associations between variables. Results: 143 patients were included in this study. 57 patients (39.8%) were underweight/normal weight, 46 (32.2%) were overweight, and 40 (28.0%) were obese. Overall, 79/143 patients (55.2%) experienced a pCR. Among patients with a pCR, median BMI was 26.3 kg/m2 (interquartile range [IQR] 23.1-30.5 kg/m2); among patients without a pCR, median BMI was 26.1 kg/m2 (IQR 23.6-30.0 kg/m2; p &amp;gt;0.9). There was no significant association between BMI category and pCR (p=0.9). Overall, 63/143 (44%) of patients experienced an irAE; 42 (29.4%) required treatment for an irAE. There were no associations between BMI and the incidence (p=0.5) or frequency (p=0.7) of irAEs. Conclusions: In this TNBC cohort treated with neoadjuvant chemo-immunotherapy, BMI was not associated with rates of pCR or irAEs. These findings highlight the divergent impact of BMI on immunotherapy response across cancer types. Confirmatory studies in independent cohorts are needed. Citation Format: Sherry Shen, Sara Myers, Yuan Chen, Stephanie Downs-Canner, Nour Abuhadra, Tiffany Traina, Mark Robson, Neil Iyengar. Body mass index and response to neoadjuvant chemo-immunotherapy among women with primary triple negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-03-06.

Abstract PS14-06: Real-World Analysis of Adverse Events in Patients with Triple Negative Breast Cancer Receiving Therapy per KEYNOTE-522

Abstract Title: Real-world analysis of adverse events in patients with triple-negative breast cancer receiving therapy per KEYNOTE-522 Background: KEYNOTE-522 was a randomized, double-blind, placebo-controlled phase 3 trial which resulted in the FDA approval of pembrolizumab with neoadjuvant chemotherapy for patients (pts) with newly diagnosed, high-risk, early-stage triple-negative breast cancer (TNBC). Given the improvement in pathological complete response (pCR) and event-free survival rates, this regimen has emerged as standard-of-care (SOC) therapy. To date, real world outcome analyses are limited. Methods: In this retrospective, multicenter study, we examined pts with early-stage TNBC who received planned treatment per KEYNOTE-522 as SOC. 16 sites were included in the analysis. IRB approval was obtained from each participating site. Number and length of treatment delays, treatment related toxicities (both chemotherapy and immune-related) of all grades, and pCR rate were collected from the electronic medical record of each participating site, and deidentified data were shared for central analysis. Results: 577 pts were included in this analysis. The median age of the cohort was 52 [range 27-77]. 457 pts had T1-2 disease and 139 had T3-4 disease. 316 pts had N0 disease and 261 had N1-3 disease. 506 pts had baseline ECOG 0, 62 had ECOG 1, and 9 had ECOG 2-3. Of the 482 patients who had surgery at the time of this analysis, 219 patients had pCR (54.5%) and 192 pts were still receiving treatment. 217 patients (37%) had an adverse drug event (ADE) causing dose reductions and 228 patients (39.5%) had to discontinue treatment early. There were 360 unplanned care visits, with 91 patients having 2+ visits. 66 patients had hospitalizations due to the regimen with 102 total hospitalizations. 179 (31%) of patients had grade 3+ immune related adverse events (irAEs), including many that are rare and potentially serious. 317 (54%) had an immune related adverse effect (see Table 1). There was no significant difference in the frequency of grade 3+ irAE based on age or body mass index. We observed no difference in residual disease between patients who discontinued treatment early and those who did not. However, if patients had an ADR causing a dose reduction, pts were significantly more likely to have residual disease (P=0.039) Conclusions: In a multicenter real-world analysis, the KEYNOTE-522 regimen was associated with a high frequency of dose reductions, early treatment discontinuations, ER visits, and hospitalizations. This may have accounted for a lower pCR rate than observed in the landmark clinical trial. Most grade 3+ irAEs occurred at greater frequency in our real-world analysis. Providers should carefully monitor for toxicity to ensure optimal patient outcomes. Table 1 Citation Format: Mara Hofherr, Katherine Clifton, Spenser January, Emily Owen, Farah Raheem, Lida A. Mina, Suganya Arunachalam Karikalan, Lauren Lyons, Meredith Watson Rose, Katherine Madden, Jerline Hsin, Aimee Keegan, Wai Yu, Shawna Kraft, Allison Schepers, Emily Armgardt, Douglas Mazewski, Alison Svoboda, Kayla Harwood, Jodi Taraba, Yonatan Resnick, Shelly Hummert, Lisa Grate, Sidney Keisner, Jacob Hobbs, Todd Davis, Kristin Bastian, Dawn Minikel, Traci White, William Adler, Avneek Singh Sandu, Fouad Boulbol, Kelsey Finch, Andrew Davis. Real-World Analysis of Adverse Events in Patients with Triple Negative Breast Cancer Receiving Therapy per KEYNOTE-522 [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 PS14-06.

Abstract PO5-03-05: Rethinking the value of pathologic complete response rate for the survival outcomes of early triple-negative breast cancer treated with neoadjuvant chemotherapy: a systematic review and network meta-analysis

Abstract Background: Neoadjuvant chemotherapy (NACT) has been more frequently used in breast cancer, but it’s controversial whether NACT or adjuvant chemotherapy (ACT) is more effective in improving survival outcomes for triple-negative breast cancer (TNBC) patients. Recent studies also proposed pathologic complete response (pCR) could not be a robust surrogate for survival outcomes in certain types of breast cancer. To address these questions, a general meta-analysis and a network meta-analysis (NMA) were conducted to compare the survival outcomes of patients with pCR, non-pCR after NACT and ACT. The cut-off pCR rate was also declared to indicate when NACT produces equivalent survival outcomes to ACT (Registration: PROSPERO CRD42022336732). Methods: Databases including PubMed, Embase, Web of science and Cochrane library were searched up to June 2023 to investigate studies comparing NACT and ACT, as well as randomized controlled trials (RCTs) comparing different regimens in NACT or ACT settingsin early operable TNBC patients. Heterogeneity was assessed using χ² based Q-test and I², combined with hazard ratios (HRs) with 95% confidence intervals (CI) computed for overall survival (OS), and disease-free survival (DFS, or event-free survival). The NMA with a Bayesian framework was conducted using both random and fixed effect model. The Weighted Least Square method and the Least Absolutely Deviation method were used to determine the cut-off pCR rates of OS and DFS. Results: A total of 35 studies involving 21 RCTs and 34143 TNBC patients were included. The general meta-analysis comprised 14 cohort studies. Eight high-quality cohort studies with propensity score matching and 21 RCTs were included in NMA. The pooled pCR rate for NACT was 42.2% (95% CI 37.8%-46.8%). Overall, the NACT cohort showed significantly worse OS and DFS than ACT cohort (HR=1.67, 95% CI 1.22-2.31; HR=1.37, 95% CI 1.14-1.64). However, patients with pCR after NACT showed improved OS than ACT (HR=0.58, 95% CI 0.50-0.66), while the patients without pCR after NACT had pooper OS than ACT (HR=2.03, 95% CI 1.88-2.19). As for DFS, there was no statistically difference between pCR after NACT and ACT groups (HR=1.04, 95% CI 0.63-1.73), while patients without pCR after NACT had significantly worse DFS than ACT (HR=2.65, 95% CI 1.98-3.55). From the NMA, the OS and DFS were better when combining modern target therapy such as Bevacizumab, PARPi, and PD-1/PD-L1 inhibitor, but not achieving pCR completely negated the benefits of newer drugs. Adding adjuvant capecitabine to patients not achieving pCR seemed to favor the OS. It was predicted that when the pCR rates were 64.7% and 44.6%, respectively, the OS and DFS of patients treated with NACT would be the same as those of patients treated with ACT. Conclusions: Higher pCR rate after NACT was associated with improved OS compared with ACT in TNBC patients. However, failure to achieve pCR after NACT resulted in worse survival outcomes than ACT. NACT had similar survival outcomes with ACT only when the pCR rate was at least 44.6%. The development of effective NACT regimens is beneficial for breast cancer patients. Citation Format: Xiaoying Qiao, Taobo Hu, Baosheng Liang, Shu Wang. Rethinking the value of pathologic complete response rate for the survival outcomes of early triple-negative breast cancer treated with neoadjuvant chemotherapy: a systematic review and network meta-analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-03-05.

Abstract PO4-17-03: Neoadjuvant chemotherapy in invasive lobular carcinoma of the breast: A retrospective study on survival outcomes

Abstract Background: Neoadjuvant chemotherapy (NAC) is a well-established component of breast cancer management. Invasive lobular carcinoma (ILC) and invasive ductal carcinoma (IDC) are often treated similarly, but many studies are demonstrating a major difference in treatment responses according to the histopathological type of cancer. Aim: To evaluate the overall survival of patients with ILC after NAC compared with adjuvant chemotherapy. Methods: This retrospective cohort study included patients treated for breast ILC between 1998 and 2016 at the Center for Breast Diseases of de CHU de Québec – Université Laval, a tertiary breast cancer center. The primary outcomes were the overall survival (OS) and the recurrence-free survival (RFS) of ILC patients receiving NAC compared with patients who received only adjuvant chemotherapy. The follow-up was censored at the last hospital contact. The secondary outcomes were the locoregional recurrence, pathological complete response (pCR), and pCR impact on survival. Results: During the study period, 265 women were treated for ILC, of which 72 had NAC, and 193 had adjuvant therapy. No significant differences were observed regarding the patient’s characteristics (age, BMI, smoking, menopausal status, and use of hormonal replacement therapy). A T4 disease was found in 29.2% of the NAC group (vs. 0 in the adjuvant group), but the N2-3 rate was lower in the NAC group (5.6% vs. 22.3%, P=0.011). More patients in the NAC group underwent mastectomy (65.3% vs. 29.5%, P&amp;lt; 0.0001) and axillary dissection (80.6% vs. 50.8%, P&amp;lt; 0.0001). Three (4.2%) patients in the NAC group achieved a pCR. The rates of radiotherapy (P=0.851) and hormonal therapy (P=0.694) were similar between the two groups. The mean follow-up was 8 years. After adjustment for age, T, N, surgery type, radiotherapy, and hormonal therapy, the NAC group showed significantly lower 10-year OS (56.2% vs. 80.7%, P&amp;lt; 0.0001) and RFS (51.8% vs. 72.7%, P=0.0004) compared with the adjuvant group. There were no differences in the 10-year local recurrence rate (90.6% vs. 93.5%, P=0.11). In a Cox regression analysis of RFS considering the previously mentioned covariables, more events in the NAC group (OR=2.52, 95%CI: 1.39-4.58, P=0.002) and patients with N2-N3 (OR=3.68, 95%IC: 2.00-6.80, P&amp;lt; 0.01). Conclusion: Despite the general belief that ILC and IDC should be treated similarly, this study strongly suggests that ILC seems to have a poorer response to NAC. Patients diagnosed with ILC might benefit from a more aggressive surgical approach followed by adjuvant chemotherapy, no matter the severity of the disease. Additional long-term prospective comparative studies are needed to support this statement and improve the management of these patients. Citation Format: Virginie Gauthier, Anne-Julie Simard, Christine Desbiens, Brigitte Poirier, Julie Lemieux, Dominique Boudreau, Dominique Leblanc, Claudya Morin, Jean-Charles Hogue, Éric Poirier. Neoadjuvant chemotherapy in invasive lobular carcinoma of the breast: A retrospective study on survival outcomes [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 PO4-17-03.

Abstract PO3-23-02: Delays in breast cancer surgery during the COVID-19 pandemic: A population-based analysis

Abstract BACKGROUND: At various times during the COVID-19 pandemic, access to operating room resources were restricted in Ontario, Canada. This resulted in triaging of all non-urgent cases, including breast cancer (BC) surgery. Recent single institution studies have identified treatment delays during the immediate pandemic time period. The objective of this study was to assess the impact of the pandemic on wait times for breast cancer surgery at a population level. METHODS: We identified patients with a BC diagnosis between January 1, 2018 and November 30, 2021 in Ontario, Canada. Three cohorts were defined based on the following time periods: pre-pandemic (baseline) (January 2018 to 14 March 2020), immediate pandemic (March 15, 2020 to June 13, 2020), and peri-pandemic (June 14, 2020 to November 30, 2021). Time to event analysis was conducted for time to a patient’s first BC surgery. A subgroup analysis was conducted for patients who underwent neoadjuvant chemotherapy (NAC). RESULTS: The study cohort consisted of 36,639 patients with a new diagnosis of BC. Of them 30,862 patients underwent surgery (84.2%) within 18 months after diagnosis. The probability of BC patients undergoing surgery each month from their date of diagnosis was significantly lower (i.e. longer wait times) for patients diagnosed in the immediate and peri-pandemic period compared to patients diagnosed in the pre-pandemic period (log-rank P &amp;lt; 0.001). At eight weeks from date of diagnosis, the probability of having had surgery was 65.1% (95% CI: 64.5-65.8%) for patients diagnosed in the pre-pandemic period, 56.1% (95% CI: 53.6-58.6%) for immediate pandemic and 59.0% (95% CI: 58.2-59.8%) for peri-pandemic. Time for 80% of patients to have BC surgery was 5.4 months in the pre-pandemic, 5.9 months in the immediate pandemic, and 6.0 months in the peri-pandemic period. Among patients who received NAC (N=6,121; 16.7% of cohort), the probability of undergoing surgery in each month from the date of diagnosis was similar for patients diagnosed in the pre and peri-pandemic periods, but was higher (i.e. shorter wait time) for the cohort of patients diagnosed during the immediate pandemic time period (log-rank P &amp;lt; 0.001). At six months from date of diagnosis, the probability of surgery for patients who received NAC was 50.7% (95% CI: 48.9-52.5%), 61.6% (95% CI: 56.6-66.6%), and 50.9% (95% CI: 49.0-52.8%) for patients diagnosed in the pre-, immediate, and peri-pandemic periods respectively. Time for 80% NAC patients to have a surgery was 7.2 months in the immediate pandemic period, shorter than the 8.2 months in the pre-pandemic and 8.0 months in the peri-pandemic periods. CONCLUSIONS: In this large population-based study of BC patients in Ontario, we identified a delay in time to surgery in the immediate pandemic period that persisted into the peri-pandemic period. However, among patients receiving NAC there was a shorter wait time during the immediate pandemic and wait times for this group have returned to pre-pandemic levels. This is likely due to surgical prioritization of this group, despite pandemic related resource restrictions. Further research is needed to explore the regional variability and how use of neoadjuvant endocrine therapy interacted with surgical treatment timelines. Citation Format: Gary Ko, Amanda Roberts, Qing Li, Ning Liu, Toni Zhong, Eitan Amir, Anne Koch, Andrea Covelli, Vivianne Freitas, Emma Reel, Antoine Eskander, Tulin Cil. Delays in breast cancer surgery during the COVID-19 pandemic: A population-based analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-23-02.

Safety and efficacy of anlotinib combined with taxane and lobaplatin in neoadjuvant treatment of clinical stage II/III triple-negative breast cancer in China (the neoALTAL trial): a single-arm, phase 2 trial

Anlotinib is a new type of tyrosine kinase inhibitor that targets vascular endothelial growth factor receptors 1/2/3, platelet-derived growth factor receptors α/β, and fibroblast growth factor receptors 1-4 and c-Kit, with a broad spectrum of inhibitory effects on tumor angiogenesis and growth. It has been proven effective in HER2-negative metastatic breast cancer, but its efficacy in early-stage triple-negative breast cancer (TNBC) is unknown. This phase 2 study aims to evaluate the efficacy and safety of adding anlotinib to neoadjuvant chemotherapy in patients with TNBC. Patients with clinical stage II/III TNBC were treated with 5 cycles of anlotinib (12mg, d1-14, q3w) plus 6 cycles of taxanes (docetaxel 75 mg/m2 ,d1, q3w or nab-paclitaxel 125 mg/m2, d1 and d8, q3w) and lobaplatin (30 mg/m2, d1, q3w), followed by surgery. The primary endpoint was pathological complete response (pCR; ypT0/is ypN0) and the secondary endpoints include breast pCR (bpCR), axillary pCR (apCR), residual cancer burden (RCB), objective response rate (ORR), survival, and safety. Exploratory endpoints were efficacy biomarkers based on Fudan University Shanghai Cancer Center Immunohistochemical (FUSCC IHC) classification for TNBC and next-generation sequencing (NGS) of DNA from tumor tissue and blood samples of patients with 425-gene panel. This trial is registered with www.chictr.org.cn (ChiCTR2100043027). From Jan 2021 to Aug 2022, 48patients were assessed and 45 were enrolled. All patients received at least one dose of study treatment and underwent surgery. The median age was 48.5 years (SD: 8.7), 71% were nodal involved, and 20% had stage III. In the intention-to-treat population, 26 out of 45patients achieved pCR (57.8%; 90% CI, 44.5%-70.3%), and 39 achieved residual cancer burden class 0-I (86.7%; 95% CI, 73.2%-94.9%). The bpCR and apCR rate were 64.4% (29/45) and 71.9% (23/32), respectively. No recurrence or metastasis occurred during the short-term follow-up. Based on the FUSCC IHC-based subtypes, the pCR rates were 68.8% (11/16) for immunomodulatory subtype, 58.3% (7/12) for basal-like immune-suppressed subtype and 33.3% (4/12) for luminal androgen receptor subtype, respectively. NGS revealed that the pCR were 77% (10/13) and 50% (14/28) in MYC-amplified and wild-type patients, respectively, and 78% (7/9) and 53% (17/32) in gBRCA1/2-mutated and wild-type patients, respectively. The median follow-up time of the study was 14.9 months (95% CI: 13.5-16.3 months). There was no disease progression or death during neoadjuvant therapy. No deaths occurred during postoperative follow-up. In the safety population (N=45), Grade 3 or 4 treatment emergent adverse events occurred in 29patients (64%), and the most common events were neutropenia (38%), leukopenia (27%), thrombocytopenia (25%), anemia (13%), and hypertension (13%), respectively. The addition of anlotinib to neoadjuvant chemotherapy showed manageable toxicity and encouraging antitumor activity for patients with clinical stage II/III TNBC. Chongqing Talents Project, Chongqing Key Project of Technology Innovation and Application Development and Chongqing Outstanding Youth Natural Science Foundation.

Impacts of tumor microenvironment during neoadjuvant chemotherapy in patients with esophageal squamous cell carcinoma.

With the advent of immune checkpoint inhibitors (ICIs), a better understanding of tumor microenvironment (TME) is becoming crucial in managing esophageal squamous cell carcinoma (ESCC) patients. We investigated the survival impact of TME status and changes in patients with ESCC who underwent neoadjuvant chemotherapy (NAC) followed by surgery (n = 264). We examined immunohistochemical status (CD4+, CD8+, CD20+, Foxp3+, HLA class-1+, CD204+, and programmed death ligand-1 [PD-L1+]) on 264 pre-NAC and 204 paired post-NAC specimens. Patients were classified by their pre- and post-NAC immune cell status and their changes following NAC. Our findings showed that pre-NAC TME status was not significantly associated with survival outcomes. In contrast, post-NAC TME status, such as low level of T cells, CD4+ T cells, and high PD-L1 combined positive score (CPS), were significantly associated with poor overall survival (OS). Notably, TME changes through NAC exerted significant survival impacts; patients with consistently low levels of T cells, low levels of CD4+ T cells, or high levels of PD-L1 (CPS) had very poor OS (3-year OS: 35.5%, 40.2%, and 33.3%, respectively). Tumor microenvironment changes of consistently low T cells, low CD4+ T cells, and high PD-L1 were independent predictors of poor OS in multivariate Cox hazards analyses, while factors indicating post-NAC status (T cells, CD4+, and PD-L1 [CPS]) alone were not. Therefore, we suggest that the consistently low T/high PD-L1 group could benefit from additional therapies, such as ICIs, and the importance of stratification by the TME, which has recently been recognized.

Clinicopathologic and molecular correlates to neoadjuvant chemotherapy-induced pathologic response in breast angiosarcoma.

Both primary and secondary breast angiosarcoma (AS) are characterized by multifocal presentation and aggressive behavior. Despite multimodality therapy, local and distant relapse rates remain high. Therefore, neoadjuvant chemotherapy (NACT) is employed to improve the R0 resection rates and survival, but its benefits remain controversial. Herein, we investigate pathologic and molecular correlates to NACT-induced histologic response in a group of 29 breast AS, 4 primary and 25 radiation-associated (RA). The two NACT regimens applied were anthracycline- and non-anthracycline-based. The pathologic response grade was defined as: I: ≤ 50%, II: 51%-90%, III: 91%-99%, and IV: 100%. An additional 45 primary AS and 102 RA-AS treated by surgery alone were included for survival comparison. The genomic landscape was analyzed in a subset of cases and compared to a cohort of AS without NACT on a paired tumor-normal targeted DNA NGS platform. All patients were females, with a median age of 31 years in primary AS and 68 years in RA-AS. All surgical margins were negative in NACT group. The NACT response was evenly divided between poor (Grades I-II; n = 15) and good responders (Grades III-IV; n = 14). Mitotic count >10/mm2 was the only factor inversely associated with pathologic response. By targeted NGS, all 10 post-NACT RA-AS demonstrated MYC amplification, while both primary AS harbored KDR mutations. TMB or other genomic alterations did not correlate with pathologic response. All four patients with Grade IV response remained free of disease. The good responders had a significantly better disease-specific survival (p = 0.04). There was no survival difference with NACT status or the NACT regimens applied. However, NACT patients with MYC-amplified tumors showed better disease-free survival (p = 0.04) compared to MYC-amplified patients without NACT. The overall survival of NACT group correlated with size >10 cm (p = 0.02), pathologic response (p = 0.04), and multifocality (p = 0.01) by univariate, while only size >10 cm (p = 0.03) remained significant by multivariate analysis.

Immunologic Factors Associated with Differential Response to Neoadjuvant Chemoimmunotherapy in Triple-Negative Breast Cancer

Background: KEYNOTE-522 resulted in FDA approval of the immune checkpoint inhibitor pembrolizumab in combination with neoadjuvant chemotherapy for patients with early-stage, high-risk, triple-negative breast cancer (TNBC). Unfortunately, pembrolizumab is associated with several immune-related adverse events (irAEs). We aimed to identify potential tumor microenvironment (TME) biomarkers which could predict patients who may attain pathological complete response (pCR) with chemotherapy alone and be spared the use of anti-PD-1 immunotherapy. Methods: Comprehensive immune profiling, including RNA-seq gene expression assessment of 395 immune genes, was performed on matched FFPE tumor samples from 22 stage I-III TNBC patients (14 patients treated with neoadjuvant chemotherapy alone (NAC) and 8 treated with neoadjuvant chemotherapy combined with pembrolizumab (NAC+I)). Results: Differential gene expression analysis revealed that in the NAC group, IL12B and IL13 were both significantly associated with pCR. In the NAC+I group, LCK and TP63 were significantly associated with pCR. Patients in both treatment groups exhibiting pCR tended to have greater tumor inflammation than non-pCR patients. In the NAC+I group, patients with pCR tended to have greater cell proliferation and higher PD-L1 expression, while in the NAC group, patients with pCR tended to have lower cancer testis antigen expression. Additionally, the NAC+I group trended toward a lower relative dose intensity averaged across all chemotherapy drugs, suggesting that more dose reductions or treatment delays occurred in the NAC+I group than the NAC group. Conclusions: A comprehensive understanding of immunologic factors could potentially predict pCR to chemotherapy alone, enabling the avoidance of the unnecessary treatment of these patients with checkpoint inhibitors.