Treatment Options For Breast Cancer Research Articles

Plasma Metabolome Signatures to Predict Responsiveness to Neoadjuvant Chemotherapy in Breast Cancer

Background: Neoadjuvant chemotherapy (NACT) has arisen as a treatment option for breast cancer (BC). However, the response to NACT is still unpredictable and dependent on cancer subtype. Metabolomics is a tool for predicting biomarkers and chemotherapy response. We used plasma to verify metabolomic alterations in BC before NACT, relating to clinical data. Methods: Liquid chromatography coupled to mass spectrometry (LC-MS) was performed on pre-NACT plasma from patients with BC (n = 75). After data filtering, an SVM model for classification was built and validated with 75%/25% of the data, respectively. Results: The model composed of 19 identified metabolites effectively predicted NACT response for training/validation sets with high sensitivity (95.4%/93.3%), specificity (91.6%/100.0%), and accuracy (94.6%/94.7%). In both sets, the panel correctly classified 95% of resistant and 94% of sensitive females. Most compounds identified by the model were lipids and amino acids and revealed pathway alterations related to chemoresistance. Conclusion: We developed a model for predicting patient response to NACT. These metabolite panels allow clinical gain by building precision medicine strategies based on tumor stratification.

GSDME-mediated pyroptosis promotes anti-tumor immunity of neoadjuvant chemotherapy in breast cancer

Paclitaxel and anthracycline-based chemotherapy is one of the standard treatment options for breast cancer. However, only about 6–30% of breast cancer patients achieved a pathological complete response (pCR), and the mechanism responsible for the difference is still unclear. In this study, random forest algorithm was used to screen feature genes, and artificial neural network (ANN) algorithm was used to construct an ANN model for predicting the efficacy of neoadjuvant chemotherapy for breast cancer. Furthermore, digital pathology, cytology, and molecular biology experiments were used to verify the relationship between the efficacy of neoadjuvant chemotherapy and immune ecology. It was found that paclitaxel and doxorubicin, an anthracycline, could induce typical pyroptosis and bubbling in breast cancer cells, accompanied by gasdermin E (GSDME) cleavage. Paclitaxel with LDH release and Annexin V/PI doubule positive cell populations, and accompanied by the increased release of damage-associated molecular patterns, HMGB1 and ATP. Cell coculture experiments also demonstrated enhanced phagocytosis of macrophages and increased the levels of IFN-γ and IL-2 secretion after paclitaxel treatment. Mechanistically, GSDME may mediate paclitaxel and doxorubicin-induced pyroptosis in breast cancer cells through the caspase-9/caspase-3 pathway, activate anti-tumor immunity, and promote the efficacy of paclitaxel and anthracycline-based neoadjuvant chemotherapy. This study has practical guiding significance for the precision treatment of breast cancer, and can also provide ideas for understanding molecular mechanisms related to the chemotherapy sensitivity.

Tanshinone I improves TNBC chemosensitivity by suppressing late-phase autophagy through AKT/p38 MAPK signaling pathway

The inhibition of autophagy is a potential therapeutic strategy to improve the chemosensitivity of triple-negative breast cancer (TNBC). In this study, we demonstrated that a natural terpenoid tanshinone I (TAN) enhanced the effectiveness of paclitaxel (PTX), at least in part, through an autophagy-dependent mechanism against TNBC. In vitro validation demonstrated that the combined therapy resulted in a synergistic decrease in the growth of TNBC cells. The chemosensitizing impact of TAN might be attributed to its inhibition of PTX-induced autophagy in the late phase by obstructing the fusion of autophagosomes and lysosomes, rather than by inhibiting lysosomal function. The findings from KEGG pathway analysis and molecular docking suggested that TAN might impact breast cancer chemoresistance primarily through the PI3K-Akt and MAPK signaling pathways. The non-canonical AKT/p38 MAPK signaling was further validated as the primary mechanism responsible for the inhibition of autophagy by TAN. In vivo study showed that the combined administration of TAN and PTX demonstrated a more significant suppression of tumor growth and autophagic activity compared to PTX monotherapy in the MDA-MB-231 xenograft nude mouse model. The safety evaluation of TAN in a zebrafish model, along with in vitro and in vivo validation, provided experimental and pre-clinical data supporting its potential as a natural adjunctive therapy in TNBC. Overall, this study suggests that the combination of TAN with PTX could provide an effective treatment option for advanced breast cancer, and targeting the AKT/p38 MAPK/late-autophagy signaling axis may be a promising approach for developing therapeutic interventions against TNBC.

Nanosuspensions in Breast Cancer Therapy: A Comprehensive Overview

Nanosuspensions offer a promising avenue for enhancing breast cancer treatment through improved drug delivery, solubility, and targeting. These colloidal dispersions contain submicron drug particles, significantly increasing surface area and enhancing drug solubility and dissolution rates. This improvement can lead to increased drug bioavailability, enabling lower doses and reduced side effects. It is also possible to engineer nanosuspensions so that they are controlled-release drugs, providing sustained therapeutic levels at the tumor site. Nanosuspensions facilitate targeted drug delivery, which is one of their key advantages. In order to minimize systemic toxicity, nanosuspensions contain targeting ligands or antibodies that adhere to the surface of nanoparticles in order to deliver drugs specifically to breast cancer cells. The nanosuspension platform also allows a combination therapy approach to be used, allowing multiple drugs to be delivered simultaneously in order to achieve synergistic effects and combat drug resistance. Nanosuspension treatments can be beneficial both therapeutically and for imaging and diagnostic purposes. Using nanoparticles labeled with imaging agents, it is possible to visualize tumors and monitor treatment responses. Nanosuspensions may reduce side effects associated with traditional chemotherapy by improving drug targeting and reducing systemic exposure. A nanosuspension represents a promising treatment option for breast cancer. Nanosuspensions must be fully exploited for their full potential to improve outcomes and quality of life for patients.

Shared genetics between breast cancer and predisposing diseases identifies novel breast cancer treatment candidates.

Current effective breast cancer treatment options have severe side effects, highlighting a need for new therapies. Drug repurposing can accelerate improvements to care, as FDA-approved drugs have known safety and pharmacological profiles. Some drugs for other conditions, such as metformin, an antidiabetic, have been tested in clinical trials for repurposing for breast cancer. Here, we exploit the genetics of breast cancer and linked predisposing diseases to propose novel drug repurposing. We hypothesize that if a predisposing disease contributes to breast cancer pathology, identifying the pleiotropic genes related to the risk of cancer could prioritize drug targets, among all drugs treating a predisposing disease. We aim to develop a method to not only prioritize drug repurposing, but also to highlight shared etiology explaining repurposing. We compile breast cancer's predisposing diseases from literature. For each predisposing disease, we use GWAS summary statistics to identify genes in loci showing genetic correlation with breast cancer. Then, we use a network approach to link these shared genes to canonical pathways, and similarly for all drugs treating the predisposing disease, we link their targets to pathways. In this manner, we are able to prioritize a list of drugs based on each predisposing disease, with each drug linked to a set of implicating pathways. Finally, we evaluate our recommendations against drugs currently under investigation for breast cancer. We identify 84 loci harboring mutations with positively correlated effects between breast cancer and its predisposing diseases; these contain 194 identified shared genes. Out of the 112 drugs indicated for the predisposing diseases, 76 drugs can be linked to shared genes via pathways (candidate drugs for repurposing). Fifteen out of these candidate drugs are already in advanced clinical trial phases or approved for breast cancer (OR = 9.28, p = 7.99e-03, one-sided Fisher's exact test), highlighting the ability of our approach to identify likely successful candidate drugs for repurposing. Our novel approach accelerates drug repurposing for breast cancer by leveraging shared genetics with its known risk factors. The result provides 59 novel candidate drugs alongside biological insights supporting each recommendation.

Trastuzumab-emtansine versus other anti-HER2 regimens in early or unresectable or metastatic HER-2 positive breast cancer: systematic review and network meta-analysis.

Motivation for the study. Treatment options for HER2-positive breast cancer were evaluated, focusing on the efficacy and safety of trastuzumab-emtansine (T-DM1) compared to other anti-HER2 therapies. Main findings. Trastuzumab-deruxtecan (T-DXd) and PyroCap emerged as promising alternatives, showing substantial improvements in progression-free survival for locally advanced or metastatic breast cancer. T-DM1 showed superior efficacy to the other treatments. Implications. Our findings could inform healthcare decision-making processes to optimize strategies for HER2-positive breast cancer, and potentially improve health outcomes and quality of life. We aimed to study the efficacy and safety of trastuzumab-emtansine (T-DM1) versus other anti-HER2 therapies in HER2+ breast cancer (BC). We performed a network meta-analysis (NMA) of randomized controlled trials (RCTs). Our study focused on patients undergoing treatment for unresectable locally advanced breast cancer (LABC) or metastatic breast cancer (mBC), which included regimens involving trastuzumab and taxanes. Additionally, we considered cases within the first 6 months of treatment for HER2+ early breast cancer (EBC). A total of 23 RCTs and 41 reports were included in our analysis. LABC and mBC showed no statistically significant difference in any of the comparisons of T-DM1 versus the other anti-HER2+ therapies. When assessing progression-free survival (PFS), trastuzumab-deruxtecan (T-DXd) and PyroCap demonstrated greater efficacy compared to other treatments (Hazard Ratio [HR]: 3.57; 95% confidence interval [CI]: 2.75-4.63 and HR: 1.82; 95% CI: 1.35-2.44; respectively), while T-DM1 alone exhibited superior effectiveness compared to LapCap (HR: 0.65; 95% CI: 0.55-0.77), TrasCap (HR: 0.65; 95% CI: 0.46-0.91), LapCapCitu (HR: 0.60; 95% CI: 0.33-1.10), Nera (HR: 0.55; 95% CI: 0.39-0.77), and Cap (HR: 0.37; 95% CI: 0.28-0.49). NMA allows a ranking based on the comparative efficacy and safety among the interventions available. Although superior to other schemes, T-DM1 showed a lower efficacy performance in PFS and overall response rate and a trend towards worse overall survival than T-DXd.

Disparities in PI3K/mTOR inhibitor use, toxicities, and outcomes among patients with metastatic breast cancer.

Novel agents such as PI3K and mTOR inhibitors (PI3K/mTORi) have expanded treatment options in metastatic breast cancer (MBC). Nevertheless, mortality rates remain disproportionately high for Black patients and patients with lower socioeconomic status. Furthermore, clinical trials for these novel agents lacked diversity, so their toxicity profile in minority populations is uncertain. We conducted a retrospective analysis of EHR-derived data from the Flatiron Health Database for patients with HR+, HER2- MBC. Multivariable logistic regression was used to evaluate factors associated with PI3K/mTORi use and toxicity outcomes. A total of 9169 patients with MBC were included in our analysis, of which 1780 (19.4%) received a PI3K/mTORi. We estimated the conditional total effect of insurance through Medicaid, and found lower odds of use of PI3K/mTORi among patients on Medicaid compared to those with commercial insurance (OR 0.73, 95% CI 0.54-0.99, p = 0.049). Odds of PI3K/mTORi use were higher for patients treated at an academic center (OR 1.28, CI 1.06-1.55, p = 0.01). Modeled as a controlled direct effect, Black/African American (Black/AA) race had no impact on odds of PI3K/mTOR use. Black/AA patients had twice the odds of developing hyperglycemia on PI3K/mTORi compared to White patients (OR 2.02, CI 1.24-3.39, p < 0.01). This analysis of real-world data suggests that the use of PI3K/mTORi is influenced by socioeconomic factors. We also found racial disparities in toxicity outcomes, with Black/AA patients having twice the risk of hyperglycemia. Our findings call for greater efforts to ensure access to novel treatments and improve their tolerability in diverse populations.

Abstract PO1-13-07: LIV-1 and Trop2 expression using Immunohistochemistry as prognostic markers in early breast cancer

Abstract Backgrounds: Antibody-drug conjugate (ADC) has emerged as treatment option for breast cancer (BC). The ASCENT and TROPiCS-02 trial of Sacituzumab Govitecan, a Trop2 ADC, gained great success in TNBC and HR+ BC. Other targets, such as LIV-1, are being investigated for TNBC and HR+ BC. The clinical trials of Ladiratuzumab, an ADC of LIV-1 Ab and MMAE, are ongoing. However, unlike Her2 protein, the predictive and prognostic role of LIV-1 and Trop-2 has not been fully investigated. Therefore, we aimed to analyze the relationship between expression level and clinicopathological features and explore the value of the markers among subtypes of BC. Methods: TMA were selected from 1,349 breast cancer specimen of patients who received curative surgery from 2008 to 2012 at Seoul National University Hospital and IHC staining was performed on the TMA using LIV-1 antibody (HPA042377 manufactured by Sigma-Aldrich, St. Louis, MO, dilution ratio of 1:300) and Trop2 antibody(HPA055067, dilution ratio of 1:75). All IHC slides were carefully evaluated by trained pathologists. IHC expression was assessed as intensity (negative:0, weak:1, moderate:2, and strong:3). A modified histochemical score(H-score) was calculated from the intensity multiplied by the percentage of positive cells. Results: A total of 1119 patients from selected samples were included. The median age was 49 (range 25-90). Most patients had early T stage disease (n=513, 569, 29, 7, for pT1, pT2, pT3, pT4, respectively). The percentage of nodal metastasis (N=687 vs 432 in pN0 vs ≥pN1, 61.4 vs 38.6%) and LVI (N= 678 vs 441 in neg vs pos, 60.6% vs 38.6%). 713 pts (63.7%) were HR+ subtype, 200(17.9%) of Her2+ and 206(18.4%) of TNBC. We divided patients into negative/low/high expression groups according to LIV-1 expression by median expression level (cutoff H-score = 100): 479 of 1119 (42.8%) LIV-1-negative; 270 (42.2%) LIV-1-low expression and 370 (57.8%) LIV-1-high. Patients with LIV-1-low or -high tumors showed better DFS (156.2 vs 158.8 vs 159.95 mo for LIV-1-negative, -low, -high, respectively; P=0.0072) and OS(157.6 vs 163 vs 165.4 mo, P=0.0029) . HR+ subgroup, (N= 193 vs 228 vs 354 for neg vs low vs high), followed overall tendency (153.4vs 158.3 vs 159.9mo, P=0.0571 in DFS, 155.6vs160.2 vs165.4mo, P=0.0627 in OS, respectively) In contrast, for patients with TNBC, LIV-1-high expression showed the worst DFS and OS. (N = 183 vs 18 vs 5 in neg vs low vs high group, 159.7 vs 160.7 vs 93.1mo, P value=0.1854 for DFS, 160.8 vs 160.7 vs 93.1 mo, P=0.0334 for OS, respectively) LIV-1 expression failed to prove a prognostic value in Her2+ BC. We also analyzed Trop2 expression by dividing patients into low/intermediate/high by the method used previously in ASCENT trial. 1009 of 1119 (n=341 in low, 363 in intermediate, 305 in high expression) patients had Trop2 expression. There was no statistically significant difference in DFS and OS among all subtypes. In multivariate analysis, neither LIV-1 or Trop-2 had a prognostic role. Conclusion: The analysis of clinicopathological findings of LIV-1 protein indicates their values for prognosis markers, especially in HR+ BC and TNBC. Trop2 expression has no prognostic role in line with previous research. Further studies are warranted to explore targetable biomarkers for the development of appropriate ADCs. Citation Format: Yeonjoo Choi, Han Suk Ryu, Jiwon Koh, Dae-Won Lee, Kyung-hun Lee, Seock-Ah Im. LIV-1 and Trop2 expression using Immunohistochemistry as prognostic markers in early breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-13-07.

Abstract PO2-02-10: Predicting the feasibility of breast conserving surgery using pre-treatment standard of care DCE-MRI: a novel clinical decision support tool for breast cancer surgical planning

Abstract Background: The decision-making process regarding breast cancer treatment options, specifically breast conserving surgery (BCS) versus mastectomy, is a complex and sensitive matter that takes into account the patient's preferences and their eligibility for BCS. A range of anatomical factors, such as tumor size, breast size, and proximity of the tumor to the skin, can influence the surgeon's recommendation regarding BCS or mastectomy. While mastectomy may be the only viable option for patients with large tumors, those with smaller tumors often have the opportunity to collaboratively decide with their surgeon on the most appropriate approach to ensure oncologic success and minimize potential cosmetic deformity. To facilitate this decision-making process, we developed a tool capable of providing informed recommendations on BCS or mastectomy based on standard of care imaging patient data. By integrating these recommendation capabilities, we aim to enhance the decision-making process and improve patient outcomes in breast cancer treatment. Methods: To assist surgeons and patients in determining a patient’s eligibility for breast conserving surgery (BCS), we developed the BCS Feasibility Score. The BCS Feasibility Score is generated from a binary classifier machine learning model and is representative of the probability that a given patient could receive BCS. The score is based solely on the output from TumorSight Viz, a software platform that uses only pre-treatment T1-weighted DCE MRI and applies a suite of deep learning algorithms to segment the patient’s disease and the surrounding breast tissues. From the multi-tissue segmentation generated using TumorSight Viz, we extracted 25 spatial morphology features to use in the model development process. The training and testing sets were a subsample of a publicly available dataset (Saha, et al, 2018). We selected patients that received either BCS or mastectomy and had a viable T1-weighted DCE MRI. Bi-lateral cases were excluded. The total training/testing set consisted of n = 749 cases, 363 of which received mastectomy and 386 who received BCS. Before model training occurred, we split 20% of the sample to use as the test set. We then trained a random forest classifier across a range of pre-set hyper-parameters, using a total of 25 features as inputs, and using 5x cross-validation in the training set. We then assessed model performance in the testing set only. Results: In the test set, 76 cases received BCS versus 74 that received mastectomy. We successfully predicted BCS in 56 out of 76 cases (74%), and mastectomy in 46 out of 74 cases (62%). Overall, we observed an AUC = 0.76 and an F1 score = 0.66, indicating moderate to strong model performance. The most important features in the model, as measured by SHAP values, included the axis aligned tumor longest dimension (mm), the closest distance between the tumor and the nipple (mm), the volume of the tumor convex hull (mL; dilated uni-centrically), and the ratio of tumor convex hull volume to breast volume. We tested the model’s performance in a fully independent holdout validation set of 579 cases. Within this validation set, 335 patients received BCS versus 244 received mastectomy. We successfully predicted BCS in 254 out of 335 cases (76%), and mastectomy in 149 out of 244 cases (61%). Overall, we observed an AUC = 0.75 and an F1 score = 0.63. Validation set performance mirrored results observed in the test set, indicating strong generalizability. In the validation set, comparing patients who underwent BCS to those who underwent mastectomy, we observed significant differences across all four of the most predictive features. Conclusion: TumorSight Viz and the BCS Feasibility Score help empower both patients and clinicians with information and tools to facilitate surgical planning decisions. Citation Format: John Pfeiffer, Bradley Feiger, Anuja Antony, Joseph Peterson. Predicting the feasibility of breast conserving surgery using pre-treatment standard of care DCE-MRI: a novel clinical decision support tool for breast cancer surgical planning [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-02-10.

Abstract PO5-05-04: Advancing Treatment and Management of Patients with HR+/HER2- Breast Cancer: Findings from a Quality Improvement Initiative

Abstract Background: With the advent of novel oral oncolytics, the cancer care delivery model for HR+/HER2- breast cancer (BC) is evolving, shifting the responsibility for medication adherence and monitoring and managing of side effects to patients and their caregivers. In this quality improvement (QI) initiative, we aimed to uncover and address gaps in patient and provider education, risk reduction, adverse event management, and shared decision-making in order to improve outcomes for HR+/HER2+ patients on oral oncolytics. Methods: From 9/2022 to 12/2022, 54 HCPs who treat breast cancer and 111 HR+/HER2- BC patients from 4 US community oncology clinics completed surveys assessing attitudes, values, and challenges related to practice patterns, education, and therapy adherence in HR+/HER2- BC. HCPs participated in audit-feedback sessions to reflect on survey results and their own practice, and developed action plans to improve care, which were implemented in subsequent collaborative patient-provider learning sessions. Results: Top reported HCP challenges in HR+/HER2- BC care include providing patient-centered supportive care measures (32%), patient adherence/lack of follow up (22%), and individualizing treatment plans (17%). Additionally, 43% of providers reported that improved collaboration across interprofessional teams would most improve care. Top reported patient challenges include worry about and/or difficulty managing side effects from treatment (26%), difficulty scheduling visits with many different HCPs/following up (24%), and difficulty communicating with healthcare teams (16%). In surveys, 28% of patients reported frequently or very frequently missing/skipping doses of oral breast cancer medication. Top reasons for missing/skipping doses included forgetting or not having it nearby (36%), cost (21%), and side effects (20%). To address the top challenges identified in baseline surveys, HCPs developed and implemented action plans, such as improving the identification of patients at high risk of recurrence, establishing patient-provider educational sessions, increasing the use of patient navigators, incorporating oral adherence toolkits, and educating patients and staff about available supportive care resources. After implementation of patient-provider collaborative education sessions at community clinics, patients reporting high levels of knowledge about BC treatment options and communicating side effects/symptoms increased from 27% to 57%, and 37% to 77%, respectively. At 60-day follow-up, 58% of patients reported taking a more active role in treatment decision-making, and 52% reported setting reminders/alarms/using apps to remember to take medication on time. Conclusions: Patient adherence to oral oncolytic medications remains a challenge in BC treatment. This quality improvement initiative uncovered underlying barriers to effective treatment management of HR+/HER2- breast cancer patients on oral oncolytics. Action plans and educational resources were developed and implemented to address identified barriers and optimize treatment management for HR+/HER2- BC. These methods and findings represent key opportunities for improvement that can be implemented in community oncology practices to improve adherence to oral oncolytics and overall HR+/HER2- breast cancer care. Citation Format: Jane Meisel, Chelsie Anderson, Ilona Dewald, Jeffrey Carter, Cherilyn Heggen, Kelly McKinnon. Advancing Treatment and Management of Patients with HR+/HER2- Breast Cancer: Findings from a Quality Improvement Initiative [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 PO5-05-04.

Abstract PO2-04-07: Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials

Abstract Background: The numerous but conflicting first-line treatment regimens for Her-2 positive advanced breast cancer necessitate a comprehensive evaluation to inform clinical decision-making. In this study, we conducted a Bayesian network meta-analysis (NMA) to compare the efficacy and safety of different interventions. Methods: We systematically searched for relevant randomized controlled trials (RCTs) in Pubmed, Embase, Cochrane Library and online abstracts published by ASCO, SABCS. NMA was performed using R software, STATA and Review Manager 5.4 to calculate and analyze the primary endpoint progression free survival (PFS), as well as the secondary endpoints of overall survival (OS), objective response rate (ORR) and adverse events (AE) higher than grade 3. Results: Out of the 8,603 manuscripts retrieved, we included 30 RCTs involving 12,045 patients in our analysis. Regarding PFS, the combination of trastuzumab with TKI was more favorable than dual-target therapy (hazard ratio=0.54, 95% [CI]: 0.40–0.72), and combination chemotherapy was superior to monotherapy (HR=0.66, 0.53-0.83). It is important to note that the addition of anthracycline did not result in improved PFS (HR=1.27, 0.87-1.86). For the HR+HER2+ population, dual-target plus endocrine therapy was more effective than single-target plus endocrine therapy (HR=0.65, 0.53-0.80). Monotherapy combined with dual-target therapy significantly improved OS and ORR compared to monotherapy with single-target therapy (HR=0.69, 0.56-0.84; OR=1.89, 1.34-2.65). A comprehensive analysis of both PFS and AE higher than grade 3 indicated that monotherapy plus dual-target therapy struck a balanced approach between effectiveness and toxicity compared to other regimens. Conclusions: Monotherapy plus dual-target therapy remains the optimal choice among all first-line treatment options for advanced breast cancer. The combination of trastuzumab with TKI demonstrated a significant improvement in PFS, but further data are warranted to confirm the survival benefit. Figure 1. Network diagrams of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. Figure 2. Forest plot of PFS, OS, ORR and adverse events higher than grade 3 in eligible experimental arms. (A): PFS of HER2+ for experimental arms. (B): PFS of HR+ and HER2+ for experimental arms. (C): OS of HER2+ for experimental arms. (D): ORR of HER2+ for experimental arms. (E): Adverse events higher than grade 3 of HER2+ for experimental arms. Figure 3. Each endpoint ranking for experimental arms. (SUCRA, surface under the cumulative ranking) (A): PFS ranking for experimental arms. (B): OS ranking for experimental arms. (C): ORR ranking for experimental arms. (D): Adverse events higher than grade 3 ranking for experimental arms. (E): Experimental arms ordered by their overall probability as the best treatment in terms of both efficacy and safety Citation Format: Junxiao Wang, Yushuai Yu, Jie Zhang, Chuangui Song. Efficacy and Safety of First-line Therapy in Patients with HER-2 positive Advanced Breast Cancer:A network Meta-analysis of Randomized Controlled Trials [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-04-07.

Abstract PO3-04-05: Efficacy and safety of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive or HER2-low expressing, metastatic breast cancer: a single-arm phase II study

Abstract Background: Current treatment options for HER2-positive (IHC 3+, or IHC 2+/FISH+) advanced or metastatic breast cancer at third-line and above have shown limited clinical benefit. There is no recommended HER2-targeting treatment for HER2-low expressing (IHC 2+/FISH-, or IHC 1+) population. RC48 (Disitamab vedotin), a newly developed antibody-drug conjugate (ADC), is comprised of three well-defined components: hertuzumab against the prominent tumor target-HER2, monomethyl auristatin E (MMAE) and a cleavable linker, with a bystanding effect in tumor cell killing. There is a lack of data on the administration of RC48 in the Chinese population. Here, we report the efficacy and safety of RC48-ADC in the advanced or metastatic breast cancer. Methods: Patients with HER2-positive or HER2-low expressing, locally advanced or metastatic breast cancer were eligible and received RC48 2.5 mg/kg every two weeks alone or combined with drugs with different anti-tumor mechanisms, such as immune checkpoint inhibitors (ICIs), tyrosine kinase inhibitors (TKIs) and antiangiogenic compounds. The primary endpoint was the objective response rate (ORR) assessed by the primary researcher. Secondary endpoints included progression-free survival (PFS), overall survival (OS), disease control rate (DCR), time to progression, and safety. Results: At the time of data cutoff (June 30, 2023), 120 chinese female breast cancer patients were enrolled and treated with RC48-ADC. 82 patients (68.3%) were HER2-positive and 38 patients (31.7%) were HER2-low expressing. At baseline, 52 patients (43.3%) had liver metastases, 40 patients (33.3%) had brain metastases, 70 patients (58.3%) had ≥3 metastases lesions, and 84 patients (70.0%) had received ≥3 prior chemotherapy regimens. In the overall population, the ORR was 38.3% (95% confidence interval [CI]: 30.0%-47.3%). The median PFS was 5.7 months (95% CI: 4.6-6.9 months). The DCR was 64.2% (95% CI: 54.9%-72.6%). In the HER2-positive subgroup, the ORR and mPFS were 42.7% (95% CI: 32.0%-54.1%) and 6.3 months (95% CI: 4.9-7.6 months). In the HER2-low expressing subgroup, the ORR and mPFS were 29.0% (95% CI: 16.0%-46.1%) and 3.6 months (95% CI: 2.0-5.3 months). In addition, the mPFS in the dual drug combination-treated group were longer than those in the single drug treatment group, with mPFS of 7.1 months (95% CI: 5.0-9.2 months) and 4.6 months (95% CI: 3.5-5.8 months), respectively. The most frequently reported treatment-related adverse events (TRAEs) were increased AST (45.8%), increased ALT (41.7%), decreased white blood cell count (25.0%), and fatigue (25%), most were grade 1-2 in severity. Conclusions: RC48-ADC showed consistent efficacy in HER2-positive and HER2-low expressing subgroups. No new safety signals were observed. Coadministration with ICIs, TKIs and antiangiogenic compounds demonstrated substantially enhanced efficacy compared to the monotherapies and could be a future direction in development of ADC. Citation Format: Fei Qu, Wei Li, Yongmei Yin, Qian Liu. Efficacy and safety of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive or HER2-low expressing, metastatic breast cancer: a single-arm phase II study [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 PO3-04-05.

Tomotherapy in synchronous and metachronous bilateral breast cancer: Clinical experience.

The objective of this research is to present our firsthand experience and provide up-to-date data for the further study of cases involving simultaneous breast irradiation using helical Tomotherapy, ©Accuray Inc. The radical treatment options for bilateral breast cancer are surgery, chemotherapy, and radiation therapy. Being that radiotherapy for bilateral breast cancer is challenging due to limitations in the geometry of modern radiotherapy equipment, helical Tomotherapy was chosen as an appropriate technique of irradiation. The retrospective review focused on the records of patients who underwent bilateral irradiation of the breast or chest wall and regional lymph nodes using helical Tomotherapy. Only four patients with bilateral breast cancer completed a radiation therapy course in our center from 2018 to 2023. Two patients underwent radical mastectomy with lymph node dissection on both sides before irradiation. For the other two patients, radical mastectomy was done after neoadjuvant chemotherapy. Acute radiation toxicity scoring was based on Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Only mild adverse effects, such as general weakness and slight skin irritation below Grade 3, were observed, with no instances of skin swelling, dryness, or pigmentation noted. Evaluation of late complications revealed tissue fibrosis in the area of the internal mammary nodes and respiratory failure with various severity. Complications and deterioration in the cardiovascular system were not observed during the follow-up period, which varied from 3 to 48months. Our results show the efficacy of using helical Tomotherapy considering positive outcomes, being that three out of four patients are in remission with low acute toxicity and late complications. There are a small number of articles describing bilateral breast cancer treatment with helical Tomotherapy. On this occasion, our data could contribute to the studies of tolerant doses for organs at risk and improve the parameters of treatment plans for bilateral breast cancer. Since the small sample of patients with bilateral breast cancer limits the study, a larger cohort of patients is essential to obtain statistically reliable results.

The inositol-requiring enzyme 1 (IRE1) endoplasmic reticulum stress pathway promotes MDA-MB-231 cell survival and renewal in response to the aryl-ureido fatty acid CTU

Current treatment options for triple-negative breast cancer (TNBC) are limited to toxic drug combinations of low efficacy. We recently identified an aryl-substituted fatty acid analogue, termed CTU, that effectively killed TNBC cells in vitro and in mouse xenograft models in vivo without producing toxicity. However, there was a residual cell population that survived treatment. The present study evaluated the mechanisms that underlie survival and renewal in CTU-treated MDA-MB-231 TNBC cells. RNA-seq profiling identified several pro-inflammatory signaling pathways that were activated in treated cells. Increased expression of cyclooxygenase-2 and the cytokines IL-6, IL-8 and GM-CSF was confirmed by real-time RT-PCR, ELISA and Western blot analysis. Increased self-renewal was confirmed using the non-adherent, in vitro colony-forming mammosphere assay. Neutralizing antibodies to IL-6, IL-8 and GM-CSF, as well as cyclooxygenase-2 inhibition suppressed the self-renewal of MDA-MB-231 cells post-CTU treatment. IPA network analysis identified major NF-κB and XBP1 gene networks that were activated by CTU; chemical inhibitors of these pathways and esiRNA knock-down decreased the production of pro-inflammatory mediators. NF-κB and XBP1 signaling was in turn activated by the endoplasmic reticulum (ER)-stress sensor inositol-requiring enzyme 1 (IRE1), which mediates the unfolded protein response. Co-treatment with an inhibitor of IRE1 kinase and RNase activities, decreased phospho-NF-κB and XBP1s expression and the production of pro-inflammatory mediators. Further, IRE1 inhibition also enhanced apoptotic cell death and prevented the activation of self-renewal by CTU. Taken together, the present findings indicate that the IRE1 ER-stress pathway is activated by the anti-cancer lipid analogue CTU, which then activates secondary self-renewal in TNBC cells.

Knowledge and Myths Regarding Breast Cancer among Women in Ernakulam District

Introduction: Breast cancer was the world’s most prevalent cancer by the end of 2020. This study aims to find out the knowledge and myths regarding breast cancer among women in Ernakulam district.Methods: A cross-sectional study was conducted in Ernakulam district in the year 2022.Adult females aged more than 20 years were the study participants. Awareness about breast cancer, associated risk factors, and screening methods was assessed using a questionnaire in the local language. The data were analyzed using SPSS software version 20.Results: The mean age of the study participants was 49.1 ± 12.2 years. 38 participants [27.14% (95% CI– 19.8, 35.3)] had adequate knowledge levels of symptoms, risk factors, diagnosis, and treatment options for breast cancer. 132 (94.3 %) women believed in at least one of the mentioned myths. Most common were theuse of deodorants or perfumes (71.4%) and tight bras (64.3%), increased the risk of breast cancer. Participants who had a family history of breast cancer (p=0.03) and those from urban areas (p = 0.024) had significantly fewer myths regarding breast cancer.Conclusion: The knowledge among women regarding breast cancer was inadequate. It’s high time that health professionals take active steps to improve knowledge regarding breast cancer through campaigns and awareness classes.

Abstract LB418: Time to adjuvant chemotherapy and its predictors among postoperative breast cancer patients at Cancer Treatment Center of Hawassa University Comprehensive Specialized Hospital in Hawassa, Ethiopia in 2022: A retrospective follow-up study

Abstract Background The incidence of breast cancer is rising and is becoming a major public health problem in Ethiopia, posing a substantial threat to countries with limited oncology centers. Adjuvant chemotherapy is the most important treatment option for breast cancer initiated after definitive surgical management. Adjuvant chemotherapy decreases the risk of breast cancer mortality, reduces the recurrence rate, and improves the long-term overall survival. The time between surgery and the first adjuvant chemotherapy appears to have an impact on the overall survival (OS) and disease-free survival (DFS) in patients with breast cancer. Objective This study aimed to determine the time to start adjuvant chemotherapy and its predictors in post-operative breast cancer patients at oncology center of Hawassa University Comprehensive Specialized Hospital between September 2020 and March 2022. Method This institution based retrospective follow-up study was conducted at the Hawassa University Comprehensive Hospital Cancer Treatment Center between September 2020 and March 2022, among all women with breast cancer. All eligible patients whose medical records were available and accessed in the hospital during the study period were enrolled. The checklists were prepared using Google Forms. The data were then exported to Excel and sent to SPSS software version 26 for data analysis. A stratified Cox regression model was used to identify potential predictors. The adjusted hazard ratio (AHR) with 95% confidence interval (CI) was reported to indicate the strength of the association. This study was conducted between February 22 and April 8, 2022. Result In this study, the median time to adjuvant chemotherapy was 69 days Interquantile range (IQR)=26) with a range of 28-157 days. Twenty (12.9%) patients started chemotherapy in less than 30 days, 36 (23.2%) patients waited for 31-60 days, 68 (43.9%) patients initiated chemotherapy within 61-90 days while 31 (20%) patients took more than 90 days to start their adjuvant chemotherapy. Patients who experienced surgical complications were 1.5 times more likely to initiate adjuvant chemotherapy earlier than those without such complications, with an adjusted hazard ratio (AHR) of 1.512 (95% CI: 1.287-3.140). Patients with a BMI classified as underweight were1.5 times high likely to receive adjuvant chemotherapy earlier (AHR 1.569, 95% CI: (1.336-3.887)). Post-operative breast cancer patients with co-morbidity had a 25% lower likelihood of receiving adjuvant chemotherapy earlier than those without comorbidity (AHR=0.751,95%CI: 0.474-0.817), and illiteracy (AHR=0.829, 95% CI: (0.458-0.950)) was also a significant predictor of time to adjuvant chemotherapy. Conclusion The duration of initiation of the adjuvant chemotherapy was longer than the recommended initiation time. Body Mass Index, presence of surgical complications, presence of comorbidity, and educational status were predictors of delayed time to adjuvant chemotherapy Citation Format: Adugna Getahun Deboch. Time to adjuvant chemotherapy and its predictors among postoperative breast cancer patients at Cancer Treatment Center of Hawassa University Comprehensive Specialized Hospital in Hawassa, Ethiopia in 2022: A retrospective follow-up study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB418.

Impact of neoadjuvant chemotherapy on the safety and long-term outcomes of patients undergoing immediate breast reconstruction after mastectomy

BackgroundIn breast cancer patients receiving neoadjuvant chemotherapy (NAC), immediate breast reconstruction (IBR) as a breast cancer treatment option remains controversial. We assessed the impact of NAC on surgical and oncological outcomes of patients undergoing IBR.MethodsThis was a retrospective multicenter study of 4726 breast cancer cases undergoing IBR. The rate of postoperative complications and survival data were compared between IBR patients who received NAC and those who did not receive NAC. Propensity score matching analysis was performed to mitigate selection bias for survival.ResultsOf the total 4726 cases, 473 (10.0%) received NAC. Out of the cases with NAC, 96 (20.3%) experienced postoperative complications, while 744 cases (17.5%) without NAC had postoperative complications. NAC did not significant increase the risk of complications after IBR (Odds ratio, 0.96; 95%CI 0.74–1.25). At the median follow-up time of 76.5 months, 36 patients in the NAC group and 147 patients in the control group developed local recurrences. The 5-year local recurrence-free survival rate was 93.1% in the NAC group and 97.1% in the control group. (P < 0.001). After matching, there was no significant difference between the two groups.ConclusionIBR after NAC is a safe procedure with an acceptable postoperative complication profile.

Thymoquinone: A novel treatment option for triple negative breast cancer

The most common treatment modes of cancer include chemotherapies along with other modes of treatment. But often resistance is developed and gruels towards the discovery of new modes of treatment for cancer. Natural products are used for ages in the treatment. One such component is thymoquinone (TQ). It has been extensively studied against cancer, especially in treating breast cancer. The review article updates its status on research against breast cancer and triple negative breast cancer. The paper describes various breast cancer (BC) treatment options in combination with TQ or alone such as heat shock 70-kDa protein 6 (HSPA6) situated on human chromosome in inhibition of BC growth, MMP-9 and MMP-2 as biomarkers in BC, use of cancer stem cells in vascular formation in solid tumor by VM (vascular mimicry) via MMP-2 and MT1-MMP genes upregulation, use of exosomes extracted from adipocyte-derived mesenchymal stem cells, cancer immunotherapy or immuno-oncology where natural killer lymphocyte cells are used to enhance innate immune response against tumors and pathogens, use of (TRAIL) tumor necrosis factor-related apoptosis-inducing ligand agonists, drugs with synergistic activity, identifying targeted genes IL17RD, and diet having natural molecules that can act potentially against cancer. The article also updates on research associated with TQ in overcoming hindrances related to its poor bioavailability making it an effective clinically acting drug molecule. Recent research indicates that TQ can be a successful candidate to eradicate cancer through its clinical interventions followed by drug design studies.

Abstract 4626: A kit targeting detection of ESR1 mutations from circulating exosomal RNA and cell-free DNA supports longitudinal studies into endocrine therapy resistance in a broadly accessible RT-qPCR format

Abstract Introduction: The most prevalent subtype of breast cancer is HR+/HER2- (positive for hormone receptor, negative for human epidermal growth factor receptor 2). For metastatic breast cancer (mBC), a frequent occurrence is resistance to the aromatase inhibitors used in endocrine therapy (ET). Resistance is mediated through mutations in the ligand binding domain of estrogen receptor 1 (ESR1). Approval of elacestrant, a second-line agent for HR+/HER2-/ESR1 mutated mBC , underscores the need for early detection of ESR1 resistance mutations. We have developed sensitive RT-qPCR reagents for targeted longitudinal studies into the emergence of ESR1 resistance mutations in plasma. This all-inclusive kit analyzes circulating exosomal RNA (exoRNA) and cell-free DNA (cfDNA) to accurately identify low copy number mutations with a rapid turnaround time. Methods: Challenge panels were constructed using blends of synthetic nucleic acids of known mutational status in a background of partially fragmented wild-type DNA from cell lines. Additionally, plasma samples collected from subjects with stage IV mBC (HR+/HER2-) on active aromatase inhibitor therapy, +/- CDK 4/6 inhibitor for a minimum of one year, were subjected to an in-house method optimized to co-enrich exoRNA and cfDNA. Multiplex RT-qPCR-based target enrichment performed on 11 ESR1 mutations and an internal control were evaluated on widely used thermal cycler and qPCR instruments. Results: We developed technology that interrogates 11 key ESR1 mutations associated with ET resistance in HR+/HER2- mBC cases. Earlier studies performed in simplex analyzed plasmid-based ESR1 mutations with detection of 10 or fewer mutant copies, estimating analytical sensitivity of at least 0.1% (5 mutant copies in a background of 5,000 WT copies). Herein, we describe the subsequent work to complete the methodology employed in the kit, including the incorporation of an endogenous control, external batch run control materials (positive, negative), deeply optimized reagents (RT, pre-amplification, qPCR), and automated analysis. We report on the results of studies into the kit’s performance characteristics against their targets: analytical sensitivity of the equivalent of 5 copies of mutation per mL plasma, high precision across replicates at 0.1% allele fraction, analytical specificity of ≥90% negative results in mutation-negative replicates, as well as workflow attributes (reduced pipetting steps and turnaround time). Conclusion: Our solution to detect ESR1 resistance mutations facilitates the generation of nucleic acid sample to results within one day using liquid biopsy samples and a multiplexed RT-qPCR. Enhancing mutation detection sensitivity by complementing cfDNA with exoRNA will facilitate future research into breast cancer treatment options. Citation Format: Justin T. Brown, Julie R. Thibert, Liangjing Chen, Melissa Church, Holli Dale, Jamie Myers, Elliot Hallmark, Megan Yociss, J Aquiles Sanchez, Kurt Franzen, Johan Skog, Gary Latham, Brian Haynes, Sarah Statt. A kit targeting detection of ESR1 mutations from circulating exosomal RNA and cell-free DNA supports longitudinal studies into endocrine therapy resistance in a broadly accessible RT-qPCR format [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4626.

Abstract 6923: Deconvolution of breast cancer dissemination and therapy resistance via single-cell transcriptional lineage tracing

Abstract Chemotherapy remains the most used systemic treatment option for triple-negative breast cancer (TNBC). Lineage tracing studies demonstrated that treatment does not significantly alter clonal composition of primary tumors (PTs). The specific transcriptional phenotype(s) conferring chemoresistance in PTs and metastasis, however, are still largely undetermined, and have not been analyzed at single-clone resolution. We first modelled clinically relevant contexts of chemoresistance in our recently published single-cell lineage tracing approach (DOI: 10.1158/0008-5472.CAN-22-2717), using the standard-of-care combination of adriamycin and cyclophosphamide (A+C) in TNBC xenografts. Treatment was administered in neoadjuvant or adjuvant settings, or both together. In all cases, surgical PT resection was followed by metastatic disease. The neoadjuvant treatment resulted into a stable disease, thus resembling a significant fraction of the treated patients. To investigate clonal and transcriptional dynamics we performed scRNAseq analysis of 12 replicates (3 matched PT-lung replicates for each condition, for a total of 24 samples). Clustering analyses revealed a separation of treatments and tissue of origin. We retrieved a large number of longitudinal clones, including rare clones with high metastatic potential, in all the experimental conditions. A+C did not significantly alter clonal abundances, neither in PTs nor in metastases. Pseudobulk transcriptional analyses revealed key transcriptional traits associated with chemoresistance. Differential expression on longitudinal clones gave insights about transcriptional features of chemoresistant and pro-metastatic clones under chemotherapy. Integration at single-clone level of cluster analysis, pseudobulk and differential expression revealed cystatin (CST) family genes as highly-enriched in the chemoresistant and pro-metastatic phenotype. We are currently validating the role of CST genes in tumor growth, dissemination and chemoresistance in vivo using a panel of specific shRNAs. In parallel, using the same experimental model, we successfully deconvoluted the metastatic cascade through a single-cell lineage tracing approach on matched PT-CTC (circulating tumor cells)-lung replicates. scRNAseq analyses of pro-metastatic, circulating and metastatic clones is ongoing. Our preliminary data showed that all the dominant clones in the metastatic lungs are also found as CTCs in the bloodstream, thus suggesting that all pro-metastatic cells are also capable of surviving in the bloodstream and reinforcing our concept of pro-metastatic clone. This approach led us to gain a complete overview around clonal and transcriptional evolution of breast cancer dissemination. Citation Format: Alberto Dalmasso, Andrea Cossa, Giulia Bertolini, Niccolò Roda, Ilaria Servidio, Francesco Antonio Tucci, Salvatore Pece, Gabriella Sozzi, Pier Giuseppe Pelicci. Deconvolution of breast cancer dissemination and therapy resistance via single-cell transcriptional lineage tracing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6923.