Neoadjuvant Chemotherapy In Breast Cancer Research Articles

Predictive analysis of breast cancer response to neoadjuvant chemotherapy through plasma metabolomics.

Preoperative chemotherapy is a critical component of breast cancer management, yet its effectiveness is not uniform. Moreover, the adverse effects associated with chemotherapy necessitate the identification of a patient subgroup that would derive the maximum benefit from this treatment. This study aimed to establish a method for predicting the response to neoadjuvant chemotherapy in breast cancer patients utilizing a metabolomic approach. Plasma samples were obtained from 87 breast cancer patients undergoing neoadjuvant chemotherapy at our facility, collected both before the commencement of the treatment and before the second treatment cycle. Metabolite analysis was conducted using capillary electrophoresis-mass spectrometry (CE-MS) and liquid chromatography-mass spectrometry (LC-MS). We performed comparative profiling of metabolite concentrations by assessing the metabolite profiles of patients who achieved a pathological complete response (pCR) against those who did not, both in initial and subsequent treatment cycles. Significant variances were observed in the metabolite profiles between pCR and non-pCR cases, both at the onset of preoperative chemotherapy and before the second cycle. Noteworthy distinctions were also evident between the metabolite profiles from the initial and the second neoadjuvant chemotherapy courses. Furthermore, metabolite profiles exhibited variations associated with intrinsic subtypes at all assessed time points. The application of plasma metabolomics, utilizing CE-MS and LC-MS, may serve as a tool for predicting the efficacy of neoadjuvant chemotherapy in breast cancer in the future after all necessary validations have been completed.

Longitudinal ultrasound-based AI model predicts axillary lymph node response to neoadjuvant chemotherapy in breast cancer: a multicenter study.

Developing a deep learning radiomics model from longitudinal breast ultrasound and sonographer's axillary ultrasound diagnosis for predicting axillary lymph node (ALN) response to neoadjuvant chemotherapy (NAC) in breast cancer. Breast cancer patients undergoing NAC followed by surgery were recruited from three centers between November 2016 and December 2022. We collected ultrasound images for extracting tumor-derived radiomics and deep learning features, selecting quantitative features through various methods. Two machine learning models based on random forest were developed using pre-NAC and post-NAC features. A support vector machine integrated these data into a fusion model, evaluated via the area under the curve (AUC), decision curve analysis, and calibration curves. We compared the fusion model's performance against sonographer's diagnosis from pre-NAC and post-NAC axillary ultrasonography, referencing histological outcomes from sentinel lymph node biopsy or axillary lymph node dissection. In the validation cohort, the fusion model outperformed both pre-NAC (AUC: 0.899 vs. 0.786, p < 0.001) and post-NAC models (AUC: 0.899 vs. 0.853, p = 0.014), as well as the sonographer's diagnosis of ALN status on pre-NAC and post-NAC axillary ultrasonography (AUC: 0.899 vs. 0.719, p < 0.001). Decision curve analysis revealed patient benefits from the fusion model across threshold probabilities from 0.02 to 0.98. The model also enhanced sonographer's diagnostic ability, increasing accuracy from 71.9% to 79.2%. The deep learning radiomics model accurately predicted the ALN response to NAC in breast cancer. Furthermore, the model will assist sonographers to improve their diagnostic ability on ALN status before surgery. Our AI model based on pre- and post-neoadjuvant chemotherapy ultrasound can accurately predict axillary lymph node metastasis and assist sonographer's axillary diagnosis. Axillary lymph node metastasis status affects the choice of surgical treatment, and currently relies on subjective ultrasound. Our AI model outperformed sonographer's visual diagnosis on axillary ultrasound. Our deep learning radiomics model can improve sonographers' diagnosis and might assist in surgical decision-making.

Factors Associated With Additional Axillary Disease in Patients With Positive Sentinel Lymph Nodes After Neoadjuvant Chemotherapy for Breast Cancer.

Background: In previous studies, breast cancer patients with positive sentinel lymph node(s) (SLN) after neoadjuvant chemotherapy (NAC) frequently had additional nonSLN involvement. Per guidelines, residual SLN disease warrants completion axillary lymph node dissection (cALND), which has increased morbidity. Given recent improvements in NAC, we hypothesized that nonSLN positivity may be lower than previously reported for certain subgroups.Methods: We retrospectively reviewed breast cancer patients who received NAC and had positive lymph nodes on SLN biopsy or targeted axillary dissection and underwent cALND at one institution in 1/2018-8/2023. Associations between nonSLN positivity and clinicopathologic factors were assessed with Fisher's exact test and multivariable logistic regression.Results: There were 122 female patients. Median age was 48years. Initially, 15 patients (12.3%) were cN0 and 107 patients (87.7%) were cN1. Largest SLN deposit was macrometastasis in 96 patients (78.7%), micrometastasis in 23 patients (18.9%), and isolated tumor cells in 3 patients (2.5%). Overall, 53 patients (43.4%) had nonSLN involvement. NonSLN positivity was higher in patients with cN1, ER+ HER2-, ypT2-3, SLN macrometastasis, and multiple positive SLN. On multivariable analysis, cN1 and ER+ HER2- remained associated with nonSLN positivity.Discussion: Among patients with positive SLN after NAC, clinically node positive and ER+ HER2- patients were more likely to have nonSLN involvement. Our findings support guidelines to consider omitting cALND in clinically node negative patients. With improving NAC, optimal axillary sampling, and radiation, omitting cALND may be safe in some clinically node positive triple negative or HER2+ patients with low volume residual disease, but further research is needed.

Predictive value of pretreatment circulating inflammatory response markers in the neoadjuvant treatment of breast cancer: meta-analysis.

Systemic inflammatory response markers have been found to have a prognostic role in several cancers, but their value in predicting the response to neoadjuvant chemotherapy in breast cancer is uncertain. A systematic review and meta-analysis of the literature was carried out to investigate this. A systematic search of electronic databases was conducted to identify studies that explored the predictive value of circulating systemic inflammatory response markers in patients with breast cancer before commencing neoadjuvant therapy. A meta-analysis was undertaken for each inflammatory marker where three or more studies reported pCR rates in relation to the inflammatory marker. Outcome data are reported as ORs and 95% confidence intervals. A total of 49 studies were included, of which 42 were suitable for meta-analysis. A lower pretreatment neutrophil-to-lymphocyte ratio was associated with an increased pCR rate (pooled OR 1.66 (95% c.i. 1.32 to 2.09); P < 0.001). A lower white cell count (OR 1.96 (95% c.i. 1.29 to 2.97); P = 0.002) and a lower monocyte count (OR 3.20 (95% c.i. 1.71 to 5.97); P < 0.001) were also associated with a pCR. A higher lymphocyte count was associated with an increased pCR rate (OR 0.44 (95% c.i. 0.30 to 0.64); P < 0.001). The present study found the pretreatment neutrophil-to-lymphocyte ratio, white cell count, lymphocyte count, and monocyte count of value in the prediction of a pCR in the neoadjuvant treatment of breast cancer. Further research is required to determine their value in specific breast cancer subtypes and to establish optimal cut-off values, before their adoption in clinical practice.

Abstract PO2-23-04: Magnetic Seeds, used to Locate the Metastatic Axillary Lymph Node placed before Neoadjuvant Chemotherapy for Breast Cancer Treatment, do not interfere the pre-surgical MRI Breast response assessment

Abstract Background: Axillary management in clinically node-positive patients who converted to ycN0 after neoadjuvant chemotherapy (NAC) for breast cancer (BC) remains under research with the aim of de-escalation of axillary lymph node dissection (ALND). A magnetic seed is one of the several positive lymph nodes marking techniques used in targeted axillary dissection (TAD) for patients with cN1 breast cancer undergoing neoadjuvant systemic therapy. It has been criticized for its potential masking effect due to the artefact it produces in the MRI sequences used to assess a proper breast response. This study evaluates if the magnetic seeds placed before NAC for guided TAD have influenced in the breast MRI response assessments. Methods: From October 2021 to June 2023, patients with cT0-4 cN1 breast cancer who were candidates for primary systemic treatment were prospectively recruited. Once a breast lesion and axillary node positivity were confirmed, a based hydrogel marker and a magnetic seed, respectively, were placed prior NAC. Once systemic treatment was completed, imaging techniques were used to assess the response, with MRI being the imaging technique of choice to assess breast response and axillary ultrasound the imaging technique of choice to assess axillary response. Surgical pathological confirmation of response in the axilla was by TAD, including sentinel lymph node and magnetic clipped node resection. Results: A total of 43 patients were included and their characteristics are shown in Table 1. In 16 patients (37%) the tumour was located in the upper outer quadrant (UOQ). In this group, the susceptibility artefact produced by the magnetic seed in the MRI created a black hole obscuring the axilla with a mean diameter of 69 mm (range: 57-76 mm). In no case did the halo interfere with the correct MRI visualisation of the breast marker. By MRI, the mean distance of the artifact halo from the breast marker or residual breast lesion was 40 mm (range: 13-79 mm). Overall, complete radiological response (ycCR) was reported in 20 patients (46%), breast only in 21 (49%) and axilla only in 38 (88%) patients. In 5 patients, preoperative axillary ultrasound revealed residual axillary disease, confirmed by FNA, lead to direct ALND. In the remaining 38 patients the axillary TAD assessment was completed. In all cases, the magnetic clipped node was successfully surgically removed. Pathological complete response (pCR) was confirmed in 9 (21%), breast only in 11 (26%) and axilla only in 13 (30%) patients. MRI diagnostic performance in detecting residual breast disease after NAC was not altered by the magnetic clipped node artifact when comparing the tumour location in the UOQ to the other quadrants (AUC 0.764 vs. 0.702; p=0.698). Conclusions: Surgical axillary staging remains the most reliable method for assessing the axillary response after NAC. Target axillary dissection guided by magnetic seed placed before NAC is an effective and accurate technique. The artifact generated in the MRI does not interfere with the pre-surgical breast response assessment after neoadjuvant systemic treatment. Table 1: Patients and tumor characteristics Citation Format: Martin Espinosa-Bravo, Joaquin Rivero Deniz, Clara Morales Comas, Javier de la Torre Fernandez de Vega, Irene Vives Rosello, Enrica Esposito, Vicente Peg Camara, María De Les Neus Rus Calafell, Ignacio Miranda Gomez, Christian Siso Raber. Magnetic Seeds, used to Locate the Metastatic Axillary Lymph Node placed before Neoadjuvant Chemotherapy for Breast Cancer Treatment, do not interfere the pre-surgical MRI Breast response assessment [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 PO2-23-04.

Abstract PO1-09-11: Racial Differences in Pathologic Complete Response Rate and Overall Survival Following Neoadjuvant Chemotherapy for Breast Cancer

Abstract Background: Neoadjuvant chemotherapy (NAC) is increasingly used in the treatment of breast cancer and has been utilized in multiple clinical trials assessing the efficacy of novel therapies. Pathologic complete response (pCR) following NAC is associated with improved survival outcomes in breast cancer and pCR is a commonly used endpoint in clinical trials. Despite improvements in breast cancer survival using modern treatment regimens, Black women continue to experience worse survival outcomes as compared to White women. The objective of this study was to evaluate the association between race and clinical outcomes, specifically pCR rate, recurrence free survival and overall survival, in patients undergoing neoadjuvant chemotherapy at our institution. Methods: We conducted a retrospective review of patients who completed at least 75% of the recommended cycles of neoadjuvant chemotherapy for breast cancer between 2010 and 2016 and underwent surgery. Receptor subtypes were defined as HR+/HER2-negative, HER2+ or triple-negative. The association between race and pCR, defined as ypT0/ypTis ypN0, and survival endpoints of overall survival and recurrence free survival were analyzed using multivariable logistic regression and Cox proportional hazard models. Results: A total of 532 women met the inclusion criteria, 323 (60.7%) were White, 188 (35.3%) were Black and 21 (3.9%) were other/unknown. Median follow-up was 65 months. The receptor subgroups consisted of 195 (36.7%) HR+/HER2-negative cancers, 193 (36.3%) HER2+ cancers and 144 (27.1%) triple-negative cancers. No significant association between race and receptor subtype (p=0.55) or pre-treatment clinical stage (p=0.96) was observed. The overall observed pCR rate was 19% for Black patients and 27% for White patients, demonstrating a significantly different pCR rate by race in multivariate analysis (odds ratio of pCR White vs Black of 1.75; p=0.02). The largest discrepancy in pCR rate between White and Black patients was within subjects with triple-negative disease (pCR rate 44% White patients vs 27% Black patients, p=0.03). There was no association between recurrence free survival and race in univariate analysis (p=0.15). A significant difference in overall survival by race was observed using multivariable Cox proportions hazard model (hazard ratio Black vs White 1.77; p=0.03). Conclusions: In this retrospective analysis of patients receiving neoadjuvant chemotherapy, Black patients experienced a significantly lower pCR rate compared to White patients, with the biggest gap identified within triple-negative breast cancers. During the study period, Black patients also experienced a lower overall survival rate compared to White patients. Differences in the ability to achieve a pCR may be a contributing factor to the worse survival outcomes of Black patients. Citation Format: Chad Livasy, Erin Donahue, Brittany Neelands, Lejla Hadzikadic-Gusic, Terry Sarantou, Mckenzie Needham, Alicia Patrick, Arielle Heeke, Antoinette Tan, Richard White. Racial Differences in Pathologic Complete Response Rate and Overall Survival Following Neoadjuvant Chemotherapy for 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 PO1-09-11.

Abstract PO1-19-06: Physical exercise during neoadjuvant chemotherapy for breast cancer as a mean to increase pathological complete response rates: the randomized Neo-ACT trial

Abstract Introduction In early breast cancer, neoadjuvant chemotherapy (NACT) is increasingly used. The proof of efficacy is pathologically complete response (pCR), i.e. the absence of invasive tumour in breast and lymph nodes at surgery. Today, pCR is a common endpoint in pharmaceutical trials since it is significantly associated with survival especially in triple-negative and HER2-positive subtypes. Apart from the mitigation of treatment-related toxicity and symptoms, physical exercise mediates anti-tumoral systemic effects associated with tumour regression in preclinical and clinical models. The aim of Neo-ACT is to test the hypothesis that physical exercise can improve pCR rates in breast cancer patients receiving NACT. Method The Neo-ACT trial is an international prospective clinical trial, randomising T1-3N0-2 breast cancer patients planned for NACT to either a home-based physical exercise intervention supported by a mobile application or routine care. The primary endpoint is pCR; secondary endpoints are patient-reported quality of life, toxicity-related outcomes, and oncological outcomes such as Residual Cancer Burden, objective radiological tumour response, as well as overall, breast cancer-specific and disease-free survival at 2, 5 and 10 years. The intervention consists of a combination of high-intensity interval and resistance training of progressing intensity, and includes two weekly 60-min exercise sessions plus at least 150 min of moderate to vigorous physical activity per week. The Neo-ACT has been registered at clinicaltrials.gov on January 11, 2022 (NCT05184582). Statistical methods Patients will be randomized in a 1:1 fashion. It is anticipated that the rate of the primary endpoint pCR will be approximately 30% in the control arm (all subtypes). We aim to increase the rate of pCR in the experimental arm to 40%, i.e. a 10 percentage points increase, which is regarded clinically relevant since it would translate into improved disease-related outcomes. With a power of 80% and an alpha of 5%, a total of 712 patients have to be included; 356 in each arm. Accounting for a drop-out of 10%, we aim to include 790 patients. Stratification at the moment of computerized randomization is based on site of treatment (hospital) and biological tumour subtype (ER+HER2-, ER+HER2+, ER-HER2+, ER-HER2-). All outcomes will primarily be analysed using an intention-to-treat approach, i.e. all study subjects will belong to the treatment group (exercise intervention or control) they were assigned to, disregarding compliance. As sensitivity analysis, all outcomes will also be analysed using a per-protocol approach, meaning that participants in the intervention group who comply with less than 65% of the prescribed physical exercise program, and participants who complete less than 40% of the planned neoadjuvant systemic therapy (around two 3-weekly courses) will be excluded from analysis. Present accrual The Neo-ACT trial has started enrolment at the first site in December 2022 and since then initiated a further five Swedish and one Finnish site. Until June 15, 2023, 26 participants had been randomized in the trial. A feasibility questionnaire is distributed via the EUBREAST network which officially supports this trial and has added the designation EUBREAST12-R. Further participating sites can be accommodated depending on volume, competing trials and language requirements for the mobile application. Contact: jana.de-boniface@ki.se Citation Format: Jana de Boniface, Cecilia Haddad Ringborg, Renske Altena, Yvonne Wengström. Physical exercise during neoadjuvant chemotherapy for breast cancer as a mean to increase pathological complete response rates: the randomized Neo-ACT trial [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 PO1-19-06.

Abstract PO3-23-03: Radar reflectors for marking of target lymph nodes in patients receiving neoadjuvant chemotherapy for breast cancer – a subgroup analysis of the prospective AXSANA (EUBREAST-03) trial

Abstract Background: Surgical staging procedures of the axilla in breast cancer patients converting from a clinically positive (cN+) to a clinically negative (ycN0) lymph node status during neoadjuvant chemotherapy (NACT) vary across countries and within individual countries. The international prospective AXSANA (EUBREAST-03) study aims at comparatively evaluating long-term outcomes of different staging procedures such as axillary lymph node dissection (ALND), sentinel lymph node biopsy (SLNB), target lymph node biopsy (TLNB) and targeted axillary dissection (TAD). The comparison of marking techniques for the target lymph node (TLN) is a secondary endpoint. In this subgroup analysis, we report on the largest yet prospective cohort of patients receiving a radar reflector for marking of the TLN prior to NACT. Methods: The AXSANA study is an international prospective cohort study including cN+ patients converting to ycN0 status and treated with different axillary staging techniques according to the standard at their treating institution. The study was initiated by the EUBREAST network and started enrollment in August 2020. Eligible patients have cT1-4c tumors, initially present with axillary lymph node metastasis and receive neoadjuvant chemotherapy. Patients converting to ycN0 status are followed up for 5 years irrespectively of the ypN status. In the present subgroup analysis, only patients with a TLN marked by a radar reflector were included. We prospectively examined the retrieval rate of radar reflectors and the identification rate of the TLN (defined as unequivocal removal of the lymph node, i.e., the presence of lymphatic tissue in the TLN specimen and/or pathological confirmation of post-NACT changes typical for metastatic lymph nodes responding to treatment). Results: A TLN was marked using a radar reflector in 74 patients prior to NACT. The median age was 52 years (range: 32-77). The most common subtype was no special type in 68 (92%) patients and invasive lobular cancer in 7 (7%) patients. Most patients (n = 44, 59%) had one suspicious node at time of diagnosis, followed by two (n = 15, 20%), three (n = 10, 14%) or ≥ four suspicious nodes (n = 5, 5%). Only one TLN was marked in 73 (99%) patients and two nodes were marked in one patient (1%). Fifteen patients (20%) had a MRI between marker placement and surgery. In 4 out of 15 cases (27%), MRI artifacts were described. However, the assessment of MRI was limited due to artifacts only in one out of these four patients (25%). Out of the 74 patients with radar reflector marked TLN, 45 (61%) had undergone final surgery at the time of analysis and 29 (39%) are still under NACT. 36 out of 45 patients (80%) who received final surgery converted to ycN0. Most patients had undergone a TAD (n = 41, 91%), followed by TLNB in 7% (n = 3) and upfront ALND in 2% of cases (n = 1). All radar reflectors were successfully removed. In 44 out of 45 patients (98%) the TLN was unequivocally identified and removed. In one patient the tissue specimen containing radar reflector consisted of fat tissue and no lymphatic tissue was identifiable, so it remains unclear whether the TLN was excised, or the reflector might have dislocated. 29 patients (65%) had converted to ypN0 status. Conclusion: To the best of our knowledge this is the largest prospective series of patients receiving a radar reflector for the marking of TLN prior to NACT for breast cancer. The removal rate of the marker and the detection rate of the target node were very high. Our data demonstrate that radar reflectors are a reliable tool for marking of target lymph nodes before neoadjuvant treatment. Citation Format: Maggie Banys-Paluchowski, Steffi Hartmann, Jana de Boniface, Oreste Davide Gentilini, Timo Basali, Elmar Stickeler, Michael Untch, Franziska Ruf, Sarah Fröhlich, Marc Thill, Michael P. Lux, Florentia Peintinger, Guldeniz Karadeniz Cakmak, Isabel Rubio, Michalis Kontos, Rosa Di Micco, Dawid Murawa, Ellen Schlichting, Bilge Aktas Sezen, Achim Rody, Dagmar Langanke, Nana Bündgen, Jose Ignacio Sanchez-Mendez, Renu Buss-Steidle, Christine Mau, Nana Buchmann, Sabine Riemer, Marit Helene Hansen, Nina Ditsch, Thorsten Kühn. Radar reflectors for marking of target lymph nodes in patients receiving neoadjuvant chemotherapy for breast cancer – a subgroup analysis of the prospective AXSANA (EUBREAST-03) trial [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 PO3-23-03.

Abstract PO5-01-04: HER2 Amplification Level and Focal/Broad Region Size as Predictors of Treatment Response in Neoadjuvant Chemotherapy and Anti-HER2 Therapy for HER2-Positive Breast Cancer

Abstract Background: Neoadjuvant chemotherapy combined with anti-HER2 therapy has become the standard treatment approach for HER2-positive breast cancer. However, not all HER2-positive patients can achieve pathological complete response after neoadjuvant therapy. This raises the question of which subset of HER2+ patients derive the greatest benefit from pre-operative HER2-targeted treatment. Therefore, this study aims to determine whether the level and amplification region size of HER2 amplification are associated with the efficacy of neoadjuvant chemotherapy combined with anti-HER2 therapy. Methods: A total of 523 breast cancer samples were collected from 2017 to 2018, among which 202 cases were HER2-positive patients. Among these, 55 HER2-positive patients received neoadjuvant chemotherapy combined with anti-HER2 targeted therapy. The amplification status of HER2 was assessed using immunohistochemistry/fluorescence in situ hybridization (IHC/FISH) and next-generation sequencing (NGS). The HER2/CEP17 ratio, determined by FISH, was used to represent the amplification level of HER2. The size of the amplification region was calculated using NGS and neighboring genes located in chr17q. Amplification regions smaller than 1 Mb were classified as focal amplification, while those larger than 1 Mb were classified as broad amplification. Results: We compared the HER2/ERBB2 status of 523 breast cancer patients using different detection methods and found a high concordance between ERBB2 amplification detected by NGS and HER2-positivity detected by IHC and FISH, with a sensitivity of 96.0%, specificity of 97.8%, and overall concordance of 97.1%. Based on the HER2/CEP17 ratio determined by FISH, we observed that using a threshold of 6 for classification, the high amplification group had a significantly higher pCR rate compared to the low amplification group (86.7% vs. 41.7%; p=0.037, odds ratio [OR]=0.121, 95% confidence interval [CI]: 0.009-0.919). Moreover, the focal amplification group showed a higher pCR rate compared to the broad amplification group (65.9% vs. 30.8%, p=0.051, OR=0.237, 95% CI: 0.045-1.035). Additionally, within the low amplification group (HER2/CEP17 &amp;lt; 6), the pCR rate was 66.7% for focal amplification and 20% for broad amplification, suggesting that focal amplification of ERBB2 may further guide clinical benefit in the low HER2/CEP17 ratio group. Conclusion: This study demonstrates a high concordance between ERBB2 amplification determined by NGS and HER2-positivity determined by IHC/FISH. High HER2/CEP17 ratio and focal amplification of ERBB2 are associated with a higher pCR rate in neoadjuvant chemotherapy combined with anti-HER2 targeted therapy. Citation Format: Ning Liao, Guochun Zhang, Xinze Lv, Kai Li, Ting Hou, Zhou Zhang. HER2 Amplification Level and Focal/Broad Region Size as Predictors of Treatment Response in Neoadjuvant Chemotherapy and Anti-HER2 Therapy for HER2-Positive 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 PO5-01-04.

Abstract PO1-27-06: HER2 Amplification Level and Focal/Broad Region Size as Predictors of Treatment Response in Neoadjuvant Chemotherapy and Anti-HER2 Therapy for HER2-Positive Breast Cancer

Abstract Background: Neoadjuvant chemotherapy combined with anti-HER2 therapy has become the standard treatment approach for HER2-positive breast cancer. However, not all HER2-positive patients can achieve pathological complete response after neoadjuvant therapy. This raises the question of which subset of HER2+ patients derive the greatest benefit from pre-operative HER2-targeted treatment. Therefore, this study aims to determine whether the level and amplification region size of HER2 amplification are associated with the efficacy of neoadjuvant chemotherapy combined with anti-HER2 therapy. Methods: A total of 523 breast cancer samples were collected from 2017 to 2018, among which 202 cases were HER2-positive patients. Among these, 55 HER2-positive patients received neoadjuvant chemotherapy combined with anti-HER2 targeted therapy. The amplification status of HER2 was assessed using immunohistochemistry/fluorescence in situ hybridization (IHC/FISH) and next-generation sequencing (NGS). The HER2/CEP17 ratio, determined by FISH, was used to represent the amplification level of HER2. The size of the amplification region was calculated using NGS and neighboring genes located in chr17q. Amplification regions smaller than 1 Mb were classified as focal amplification, while those larger than 1 Mb were classified as broad amplification.&amp;gt; Results: We compared the HER2/ERBB2 status of 523 breast cancer patients using different detection methods and found a high concordance between ERBB2 amplification detected by NGS and HER2-positivity detected by IHC and FISH, with a sensitivity of 96.0%, specificity of 97.8%, and overall concordance of 97.1%. Based on the HER2/CEP17 ratio determined by FISH, we observed that using a threshold of 6 for classification, the high amplification group had a significantly higher pCR rate compared to the low amplification group (86.7% vs. 41.7%; p=0.037, odds ratio [OR]=0.121, 95% confidence interval [CI]: 0.009-0.919). Moreover, the focal amplification group showed a higher pCR rate compared to the broad amplification group (65.9% vs. 30.8%, p=0.051, OR=0.237, 95% CI: 0.045-1.035). Additionally, within the low amplification group (HER2/CEP17 &amp;lt; 6), the pCR rate was 66.7% for focal amplification and 20% for broad amplification, suggesting that focal amplification of ERBB2 may further guide clinical benefit in the low HER2/CEP17 ratio group. Conclusion: This study demonstrates a high concordance between ERBB2 amplification determined by NGS and HER2-positivity determined by IHC/FISH. High HER2/CEP17 ratio and focal amplification of ERBB2 are associated with a higher pCR rate in neoadjuvant chemotherapy combined with anti-HER2 targeted therapy. Citation Format: Ning Liao, Guochun Zhang, Xinze Lv, Kai Li, Ting Hou, Zhou Zhang. HER2 Amplification Level and Focal/Broad Region Size as Predictors of Treatment Response in Neoadjuvant Chemotherapy and Anti-HER2 Therapy for HER2-Positive 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 PO1-27-06.

Abstract PO3-12-08: Hypersensitivity reactions to paclitaxel and carboplatin in breast cancer: safety and effectiveness of desensitization

Abstract Introduction. Taxanes and platinums are first line treatment of breast cancer for early stages and metastatic disease and constitute the most commonly implicated chemotherapeutics in hypersensitivity reactions.1 Clinical manifestations range from mild skin reactions to anaphylaxis.2 Hypersensitivity reactions (HSR) to paclitaxel and carboplatin occur in a significant percentage of patients, with estimates of 30% and 40% respectively,3,4,5 leading to discontinuation of treatment.6 Using alternative drugs can be poorly tolerated or much less effective, entailing to high morbidity and mortality.7 Desensitization is the procedure performed to achieve a tolerance to the drug to which a HSR previously occurred, in order to maintain first-line treatment.8 The evaluation of the oncological response remains in the importance of assessing the shrinkage of the tumor and the time of progression of the disease.9 Objective: To describe the hypersensitivity reactions to paclitaxel and carboplatin, and the safety and effectiveness of desensitization protocols after anaphylaxis in patients with breast cancer. Materials and Methods: Original, retrospective, descriptive, and analytical study, approved by the Bioethics and Research Committee ON23-00016 code, included patients &amp;gt;18 years with breast cancer who developed a hypersensitivity reaction to first-line chemotherapy and performed a 3-bag-12-step desensitization according to the Brigham and Women's Hospital, Dana Farber Institute, Boston protocol. Results: Forty-five desensitization to paclitaxel or carboplatin were performed in 8 women with breast cancer, mean age 38.6 years. 6 patients developed HSR to paclitaxel, 83% of which were in the first application, and 2 patients developed HSR to carboplatin after several cycles. The most predominant symptom of HSR was cutaneous in 87% of the cases, and all patients presented cardiovascular HSR to paclitaxel. No patients developed HSR during desensitization. Currently, only 1 patient developed disease progression, while the rest presented a complete response to treatment. Discussion. HSR to paclitaxel appear in the 1-2 cycle,10 while to platinums after various exposures ( &amp;gt;6 cycles) similar to our study.3,4 The symptoms associated with paclitaxel are cardiovascular10,11 while urticaria is the most frequent in carboplatin.3,11 The desensitization protocol implemented did not develop HSR in any of the patients. Neoadjuvant chemotherapy in breast cancer has been shown to yield better disease-free interval results alongside improved pathological response.12 Conclusions. The program implemented in our hospital's chemotherapy desensitization clinic, replicating the model of the Dana-Farber Cancer Institute, Brigham, and Women's Hospital in Boston, has enabled cancer patients to continue with first-line treatment, thus improving their prognosis and quality of life, opening new areas of opportunity in the multidisciplinary management of these patients to improve overall survival. Characteristics of patients with hypersensitivity reactions HSR: hypersensitivity reactions ND: No data m: months yrs.: years Desensitization protocol to Paclitaxel IV (300 mg) IV: intravenous mg: milligram mL: milliliter h: hour Citation Format: Rosalaura V. Villarreal-González, Oscar Vidal-Gutiérrez, Javier A. Martínez-Moyano, Marianela Madrazo-Morales, Kathia S. Sáenz-Cantú, Patricia Rodríguez-Niño. Hypersensitivity reactions to paclitaxel and carboplatin in breast cancer: safety and effectiveness of desensitization [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 PO3-12-08.

Abstract PO4-08-01: Methylsterol monooxygenase 1 (MSMO1) modulates endoplasmic reticulum stress through cholesterol metabolic reprogramming to alter chemotherapy sensitivity in breast cancer

Abstract Background Endoplasmic reticulum stress (ER stress) is a process in which cells activate unfolded protein response and other signaling pathways in response to misfolded and unfolded protein aggregation and calcium ion balance disturbance in the endoplasmic reticulum cavity. Depending on the intensity of endoplasmic reticulum stress, it can not only induce chaperone expression to play a protective effect, but also induce apoptosis independently. Metabolic reprogramming is one of the characteristics of tumor, which refers to the metabolic changes that cells make in response to various stimuli. Here, we demonstrate that methylsterol monooxygenase 1 (MSMO1) regulates cellular cholesterol metabolism and influences breast cancer susceptibility to chemotherapy by regulating the relative intracellular T-MAS content. Methods RNA-seq was performed on core needle biopsy samples from 26 patients receiving neoadjuvant chemotherapy for breast cancer to screen for genes that may influence neoadjuvant chemotherapy sensitivity. Cell proliferation, CCK8 assay and apoptosis assay were performed for MSMO1 phenotype study. Transmission electron microscopy (TEM) was conducted to visualize the structure of endoplasmic reticulum. Western Blot was used to detect the activation level of the unfolded protein response pathway. The relative content of sterols in MSMO1 knockdown cells was detected by targeted lipid mass spectrometry. AO/PI staining of breast cancer organoids was performed to verify the effect of MSMO1 metabolic substrate T-MAS on chemotherapy drug sensitivity. Results RNA-seq of core needle biopsy samples from breast cancer patients receiving neoadjuvant chemotherapy suggested that MSMO1 was highly expressed in non-pCR patients, and clinical survival data suggested that MSMO1 was associated with poor prognosis in patients with all types of breast cancer, suggesting that MSMO1 might be related to chemotherapy sensitivity of breast cancer. Phenotypic experiments revealed that MSMO1 regulates chemotherapy sensitivity of breast cancer both in vivo and in vitro. Ectopic overexpression of MSMO1 promoted cancer cell resistance to chemotherapy. To uncover the underlying mechanisms, RNA-seq of MSMO1 knock-down cells were carried out and identified that MSMO1 was associated with ER stress. TEM and western blot assay indicated that downregulation of MSMO1 expression leads to endoplasmic reticulum swelling and activation of the unfolded protein response. Considering that MSMO1 is a cholesterol metabolizing enzyme, targeted lipids mass spectrometry was performed to detect the changes in the contents of various intermediate metabolites in the cholesterol pathway, which indicated that the relative content of T-MAS, a metabolic substrate of MSMO1, was significantly up-regulated in MSMO1 knockdown cells. Then, in order to verify whether this metabolite can independently regulate ER stress, breast cancer cells were given T-MAS externally, and TEM and Western Blot analysis indicated that T-MAS could induce ER stress and activate the unfolded protein response independently. Apoptosis assay and AO/PI staining of breast cancer organoids revealed that T-MAS can improve the sensitivity of breast cancer to chemotherapy drugs. Conclusion In summary, these results shed light on the role of MSMO1 in cholesterol metabolism reprogramming, which adjust the endoplasmic reticulum stress state of cells by changing the relative content of intracellular T-MAS, and thereby influencing the sensitivity of breast cancer chemotherapy. As an intermediate metabolite of cholesterol metabolism, T-MAS has potential clinical application value of chemotherapy sensitization. Citation Format: Hengyu Ren, Liren Wangxu, Yayun Chi, Jiong Wu. Methylsterol monooxygenase 1 (MSMO1) modulates endoplasmic reticulum stress through cholesterol metabolic reprogramming to alter chemotherapy sensitivity in 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 PO4-08-01.

Abstract PO4-03-04: Characterization of Gut Microbiome of patients with early-stage breast cancer treated with neoadjuvant chemotherapy

Abstract Objective: The gut microbiome (GM) has been identified as one of the major environmental factors that can regulate the development and maintenance of the immune system. In oncology, while the importance of GM has been evaluated in more immunogenic tumors such as melanoma, lung carcinoma and clear cell carcinoma, its importance in early-stage breast cancer (eBC) is underexplored. The aim of this study was to characterize the GM of patients with eBC who underwent neoadjuvant chemotherapy (NACT) and to evaluate its association with clinicopathologic prognostic factors and outcomes. Methods: This was a prospective study conducted at two Brazilian institutions. Fecal samples were collected at baseline (time 1) and prior to surgery (time 2) from 55 patients who received NACT with anthracycline/taxane. Gut microbiome was analyzed by 16S rRNA amplicon sequencing to characterize the α (InvSimpson index) and β (weighted UniFrac distance metric) diversity, as well as taxonomic composition. Clinicopathologic prognostic factors were retrieved from medical records. Pathological complete response (pCR) was defined as the absence of invasive carcinoma in breast and axillary nodes (ypT0/Tis ypN0). Stromal tumor-infiltrating lymphocytes (sTIL) were reported according to the TIL working group criteria. Information about prior use (&amp;lt; 60 days before stating on NACT) of antibiotic (ATB) was obtained directly from patients. Statistical significance was set at P ≤ 0.05 and analysis of composition of microbiomes (ANCOM-BC2) was used to identify enriched genera with p-values adjusted using FDR correction ≤ 0.25. Results: Median age was 49 years (range 31-73). Eleven patients (20%) reported prior antibiotic use at baseline. About 34.5% of patients had HR+/HER2- tumors, 45.4% had triple negative breast cancer (TNBC), and 20% had HER2-positive breast cancer. Fourteen (25%) patients achieved a pCR. Out of 55, 47 (85.4%) had sTIL information. There was no significant difference in alpha diversity (p = 0.6) or beta-diversity (p = 0.8) between the pCR and residual disease group nor within clinical pathologic factors (age, staging, histological tumor grade, subtype of breast cancer based on IHC, sTIL). The most abundant taxon in both time 1 and time 2 were the same (Blautia at genus level, Lachnospiraceae at family level, and Lachnospirales at order level), and longitudinal samples collected during NACT showed no significant changes in GM composition. At baseline, we found an enrichment for Clostridia sp. among patients who did not use ATB (p &amp;lt; 0.05, pFDR ≤ 0.25). Additionally, we found enrichment for Bifidobacterium (p &amp;lt; 0.05, pFDR ≤ 0.25) among patients with HER2 subtype who presented residual disease. Conclusions: Gut microbiome analysis in early breast cancer is feasible and to our knowledge, this is the first study to evaluate the intestinal microbiota of Brazilian patients with breast cancer. We did not observe any significant association between GM diversity and taxonomic composition with clinical pathologic factors and pCR in this study, nor did we observe changes in the ecological balance of the GM following NACT in breast cancer. Further studies are needed to explore the potential influence of the gut microbial ecosystem on tumor biology and response to neoadjuvant chemo-immunotherapy. Citation Format: Ludmila Thommen, Vitor Heidrich, Rosângela Vieira de Andrade, Luiza Nardin Weis, Maria Sueli Soares Felipe, Melissa Lole Da Cas Vita, Thiago David Alves Pinto, Anamaria Camargo, Romualdo Barroso-Sousa. Characterization of Gut Microbiome of patients with early-stage breast cancer treated with 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 PO4-03-04.

Predicting response to neoadjuvant chemotherapy in breast cancer by biomechanics quantified with magnetic resonance elastography

Predicting response to neoadjuvant chemotherapy in breast cancer by biomechanics quantified with magnetic resonance elastography

Evolving practice changes in neoadjuvant chemotherapy for breast cancer, in a district general hospital

Evolving practice changes in neoadjuvant chemotherapy for breast cancer, in a district general hospital

Comprehensive analysis of plasma methylome reveals distinct patterns of methylation changes between responders and non-responders to neoadjuvant chemotherapy in breast cancer

Comprehensive analysis of plasma methylome reveals distinct patterns of methylation changes between responders and non-responders to neoadjuvant chemotherapy in breast cancer

Research progress on ultrasound medicine in diagnosis and evaluation of chemotherapy effect of breast cancer

Breast cancer has the highest incidence rate among cancers in the world and is the main cause of death among female cancer patients around the world. The progress of ultrasound technology has continuously improved the ability to identify the shape and microvessels of breast masses. It plays an important role in the differentiation of benign and malignant breast masses and is the main auxiliary diagnostic method for breast cancer. The widespread implementation of neoadjuvant chemotherapy for breast cancer has improved the survival rate of patients. Evaluating the efficacy after chemotherapy and adjusting chemotherapy strategies as needed can help improve the prognosis of patients. Ultrasound can conduct multi-parameter measurements of breast tumor hardness, blood flow velocity and vascular distribution, which can be applied to evaluate the efficacy of neoadjuvant chemotherapy for breast cancer. This article reviewed the application and research progress of multi-modal ultrasound in the diagnosis and evaluation of chemotherapy efficacy of breast cancer.

One-step abductive multi-target learning with diverse noisy samples and its application to tumour segmentation for breast cancer

Recent studies have demonstrated the effectiveness of the combination of machine learning and logical reasoning, including data-driven logical reasoning, knowledge driven machine learning and abductive learning, in inventing advanced technologies for different artificial intelligence applications. One-step abductive multi-target learning (OSAMTL), an approach inspired by abductive learning, via simply combining machine learning and logical reasoning in a one-step balanced multi-target learning way, has as well shown its effectiveness in handling complex noisy labels of a single noisy sample in medical histopathology whole slide image analysis (MHWSIA). However, OSAMTL is not suitable for the situation where diverse noisy samples (DiNS) are provided for a learning task. In this paper, giving definition of DiNS, we propose one-step abductive multi-target learning with DiNS (OSAMTL-DiNS) to expand the original OSAMTL to handle complex noisy labels of DiNS. Applying OSAMTL-DiNS to tumour segmentation for breast cancer in MHWSIA, we show that OSAMTL-DiNS is able to enable various state-of-the-art approaches for learning from noisy labels to achieve more rational predictions. We released a model pre-trained with OSAMTL-DiNS for tumour segmentation in HE-stained pre-treatment biopsy images in breast cancer, which has been successfully applied as a pre-processing tool to extract tumour-associated stroma compartment for predicting the pathological complete response to neoadjuvant chemotherapy in breast cancer.

Abstract LB242: Prediction of patient response to neoadjuvant chemotherapy in breast cancer from their deconvolved tumor microenvironment transcriptome

Abstract Introduction: The tumor microenvironment (TME) is a complex and dynamic ecosystem that plays critical roles in tumor development and clinical outcome. While the multifarious cellular interactions within the TME have been extensively studied with a significant emphasis on immunotherapy, understanding its role in chemotherapy outcome remains less explored. To this end, we present a novel generic computational framework named DECODEM (DEcoupling Cell-type-specific Outcomes using DEconvolution and Machine learning). DECODEM facilitates the exploration of the association of cell-type-specific gene expression profiles with the effectiveness of neoadjuvant chemotherapy (NAC) in treating breast cancer (BC). This approach holds promise for elucidating the nuanced ways in which the TME can modulate therapeutic efficacy, potentially paving the way for more personalized and effective cancer treatments. Methods: DECODEM employs cellular deconvolution of bulk transcriptomics to extract cell-type-specific gene expression profiles within the TME, and subsequently harnesses machine learning to construct cell-type-specific predictors of clinical outcomes. Utilizing DECODEM, we analyzed three publicly available cohorts of HER2-negative BC patients who received NAC. We assessed the predictive capabilities of the individual cell types as well as their collective influence, benchmarking against a state-of-the-art predictor that employs both clinical and transcriptomic features. We corroborated our findings in a single-cell (SC) transcriptomics cohort of patients with triple negative breast cancer (TNBC) undergoing chemotherapy. Further, we expanded DECODEM to DECODEMi, which accounts for cell-cell interactions (CCIs) among the predominant cell types, offering potential insights into the mechanistic processes governing clinical responses. Results: Our analysis indicated that the heterogeneous composition of the TME is crucial for chemotherapy response prediction in HER2-negative BC, beyond the influence of malignant cells alone. The key insights from our study are as follows:1. Gene expression of immune cells (myeloid, plasmablasts, B-cells) and stromal cells (endothelial, normal epithelial, cancer-associated fibroblasts) displayed comparable-to-superior predictive powers over both bulk expression and the state-of-the-art predictor.2. The predictive accuracy is further augmented by multi-cell-type ensembles, with a triad ensemble comprising endothelial, myeloid, and plasmablast cells achieving the highest predictive accuracy across multiple cohorts.3. DECODEMi can effectively capture the regulatory impact of CCIs (validated in a SC dataset sourced from the SC-TNBC cohort) and has identified novel CCIs likely to influence chemotherapy response in HER2-negative BC. Conclusion: We provide an unprecedented computational methodology to quantitatively assess the cell-type-specific influences of the TME on clinical outcome. Our analysis offers insights into the complex interactions among TME cells and their correlation with chemotherapy efficacy in HER2-negative BC, thereby enriching the knowledge base of BC treatment effectiveness. Citation Format: Saugato Rahman Dhruba, Sahil Sahni, Binbin Wang, Di Wu, Yael Schmidt, Eldad Shulman, Sanju Sinha, Stephen-John Sammut, Carlos Caldas, Kun Wang, Eytan Ruppin. Prediction of patient response to neoadjuvant chemotherapy in breast cancer from their deconvolved tumor microenvironment transcriptome [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 LB242.

Noninvasive Artificial Intelligence System for Early Predicting Residual Cancer Burden during Neoadjuvant Chemotherapy in Breast Cancer.

To develop an artificial intelligence (AI) system for the early prediction of residual cancer burden (RCB) scores during neoadjuvant chemotherapy (NAC) in breast cancer. RCB III indicates drug resistance in breast cancer, and early detection methods are lacking. This study enrolled 1048 patients with breast cancer from four institutions, who were all receiving NAC. Magnetic resonance images were collected at the pre- and mid-NAC stages, and radiomics and deep learning features were extracted. A multitask AI system was developed to classify patients into three groups (RCB 0-I, II, and III ) in the primary cohort (PC, n=335). Feature selection was conducted using the Mann-Whitney U- test, Spearman analysis, least absolute shrinkage and selection operator regression, and the Boruta algorithm. Single-modality models were developed followed by model integration. The AI system was validated in three external validation cohorts. (EVCs, n=713). Among the patients, 442 (42.18%) were RCB 0-I, 462 (44.08%) were RCB II and 144 (13.74%) were RCB III. Model-I achieved an area under the curve (AUC) of 0.975 in the PC and 0.923 in the EVCs for differentiating RCB III from RCB 0-II. Model-II distinguished RCB 0-I from RCB II-III, with an AUC of 0.976 in the PC and 0.910 in the EVCs. Subgroup analysis confirmed that the AI system was consistent across different clinical T stages and molecular subtypes. The multitask AI system offers a noninvasive tool for the early prediction of RCB scores in breast cancer, supporting clinical decision-making during NAC.