Survival Of Breast Cancer Patients Research Articles

Functional hemodynamic imaging markers for the prediction of pathological outcomes in breast cancer patients treated with neoadjuvant chemotherapy.

Achieving pathologic complete response (pCR) after neoadjuvant chemotherapy (NACT) is a significant predictor of increased likelihood of survival in breast cancer patients. Early prediction of pCR is of high clinical value as it could allow personalized adjustment of treatment regimens in non-responding patients for improved outcomes. We aim to assess the association between hemoglobin-based functional imaging biomarkers derived from diffuse optical tomography (DOT) and the pathological outcome represented by pCR at different timepoints along the course of NACT. Twenty-two breast cancer patients undergoing NACT were enrolled in a multimodal DOT and X-ray digital breast tomosynthesis (DBT) imaging study in which their breasts were imaged at different compression levels. Logistic regressions were used to study the associations between DOT-derived imaging markers evaluated after the first and second cycles of chemotherapy, respectively, with pCR status determined after the conclusion of NACT at the time of surgery. Receiver operating characteristic curve analysis was also used to explore the predictive performance of selected DOT-derived markers. Normalized tumor HbT under half compression was significantly lower in the pCR group compared to the non-pCR group after two chemotherapy cycles (). In addition, the change in normalized tumor upon reducing compression from full to half mammographic force was identified as another potential indicator of pCR at an earlier time point, i.e., after the first chemo cycle (). Exploratory predictive assessments showed that AUCs using DOT-derived functional imaging markers as predictors reach as high as 0.75 and 0.71, respectively, after the first and second chemo cycle, compared to AUCs of 0.50 and 0.53 using changes in tumor size measured on DBT and MRI. These findings suggest that breast DOT could be used to assist response assessment in women undergoing NACT, a critical but unmet clinical need, and potentially enable personalized adjustments of treatment regimens.

Conditional survival of male breast cancer

Background The incidence of male breast cancer has been increasing in recent years; however, the long-term survival outcomes of diagnosed patients remain uncertain. This study was designed to evaluate the conditional survival of male breast cancer patients and to predict the future survival of patients through the conditional nomogram, to provide important suggestions for clinical decision-making. Methods Retrospective data from the SEER database included 3600 male breast cancer patients, divided into training and validation groups (7 : 3 ratio). Overall survival rates were calculated using Kaplan–Meier analysis. Conditional survival analysis described survival at specific years. Time-dependent multivariate Cox analysis identified prognostic factors’ impact. The conditional survival nomogram model predicted real-time survival rates. Results Over time, the 5-year real-time survival rate of patients gradually improved, increasing from 70.5 to 74.8, 79.4, 85.8, and 92.9% (respectively, representing 5-year survival rates of 1–4 years after diagnosis). In addition, the improvement in conditional survival rate CS5 showed a nonlinear trend. After 5 years of diagnosis, age, tumor size, and tumor stage had a sustained impact on patient prognosis. Finally, a conditional survival nomogram was constructed to predict the 10-year survival rate in real time. Conclusion Five years after diagnosis, the conditional survival rate of male patients with breast cancer has improved, but it is not nonlinear. In the first 5 years after diagnosis, patients with older age, larger tumor size, poorer tumor stage, and distant metastasis should be actively followed up and treated to improve their long-term survival.

Abstract PO4-16-06: From Real-World Data to Improved Outcomes: Examining the Impact of Trastuzumab Disparities on Pathological Complete Response and Long-Term Survival in HER-2 Positive Breast Cancer Patients within the Brazilian Public Health System

Abstract Introduction: Equitable access to healthcare is a fundamental principle of public health, aiming to ensure that all individuals have the opportunity to receive effective treatments. However, disparities in access to healthcare still persist in many countries, including Brazil. These disparities can have significant impacts on the health and well-being of patients, particularly in the case of breast cancer treatment. Neoadjuvant chemotherapy (NAC) has been increasingly used for the treatment of breast cancer, encompassing conditions ranging from locally advanced tumors to early-stage triple-negative and HER-2 positive tumors. Objectives: The aim of this study is to evaluate the impact of disparities in the use of trastuzumab (Herceptin) within the Brazilian public health system on pathological complete response (pCR), overall survival (OS), and disease-free survival (DFS). We aim to investigate whether variations in access to trastuzumab treatment influence the achievement of pCR and impact long-term survival outcomes in breast cancer patients. Methods: This retrospective, multicenter cohort study included female patients over 18 years of age with a diagnosis of non-metastatic breast cancer undergoing NAC. pCR was defined as the absence of residual invasive or in situ tumor in the breast and axilla. As an exploratory real-world data study, no confirmatory hypothesis was established, thus no corrections for multiple comparisons were necessary. Overall survival (OS) and disease-free survival (DFS) were estimated using the Kaplan-Meier method, calculated at five years. The study was approved by the Research Ethics Committee with registration number CAAE 64633422.4.0000.5463. Results: Between 2011 and 2020, a total of 1,891 patients were included in the study, of whom 454 (22.9%) were HER-2 positive. The pCR rate was 25.7%. Trastuzumab was accessed by 291 (64.1%) patients (p < 0.001). Among those who received trastuzumab, pCR was observed in 105 (36.1%) patients, compared to 12 (7.6%) in those who did not have access to trastuzumab (p < 0.001). OS in HER-2 positive patients was 90.1% with pCR and 64.5% without pCR (log-rank p < 0.001), while DFS was 89.2% with pCR and 68.2% without pCR (log-rank p = 0.003). Evaluating OS and DFS in patients who received trastuzumab versus those who did not, OS with trastuzumab and pCR was 94.3% and without pCR was 89.5% (log-rank p < 0.001); OS without trastuzumab and pCR was 83.3% and without pCR was 58.2% (log-rank p < 0.001). DFS in patients who received trastuzumab and achieved pCR was 94.5% and without pCR was 90.5% (log-rank p = 0.05), whereas without trastuzumab and pCR was 79.9% and without pCR was 62.1% (log-rank p = 0.001). Conclusion: These findings underscore the significant impact of disparities in trastuzumab utilization within the Brazilian public health system on pCR rates and long-term survival outcomes in HER-2 positive breast cancer patients. Access to trastuzumab was associated with higher pCR rates and improved overall and disease-free survival rates. Ensuring equitable access to targeted therapies is crucial for improving treatment response and long-term outcomes in breast cancer patients. Table 1 Clinicopathological characteristics of patients Legend: AJCC, American Joint Committee on Cancer; IDC, invasive ductal carcinoma; ILC, invasive lobular carcinoma; HR hormonal receptor. Table 2 - NAC schemas and correlation with pCR. AC-T, doxorubicin + cyclophosphamide – taxane; AC-TH, doxorubicin + cyclophosphamide – taxane+herceptin. Citation Format: Marcelo Antonini, Andre Mattar, Gabriel Pannain, Fernanda Grace Bauk Richter, Andressa Amorim, Marina Diogenes, Odair Ferraro, Luiz Gebrim, Reginaldo Coelho Lopes, Juliana Real. From Real-World Data to Improved Outcomes: Examining the Impact of Trastuzumab Disparities on Pathological Complete Response and Long-Term Survival in HER-2 Positive Breast Cancer Patients within the Brazilian Public Health System [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 PO4-16-06.

Abstract PO3-04-04: Long term survival of metastatic HER2 positive breast cancer patients with no radiographic evidence of disease (NED) on HER2 antibody therapy

Abstract Introduction A small proportion of women with human epidermal growth receptor 2 (HER2) positive metastatic breast cancer (mBC) achieve “no evidence of disease” (NED) status with HER2 monoclonal antibody therapy. Patients who achieve NED status have excellent long term outcomes with overall (OS) and progression free survival (PFS) rates greater than 95%. Presently there are no reliable biologic or clinical factors which are predictive of NED. It is also unclear in NED patients when it would be safe to discontinue therapy. Therefore, even in HER2+ mBC NED patients, HER2 therapy is often continued indefinitely. In this study, we characterize clinical outcomes in HER2+ mBC patients who achieved NED status and received HER2 antibody therapy for 5+ years. Methods We conducted a retrospective analysis of patients at a U.S. academic medical center. Patients with HER2+ mBC who had received at least 5 years of either trastuzumab or trastuzumab/pertuzumab (from 2014- 2023) were identified for our NED cohort. For a non-NED comparator group, we identified women with stage IV HER2+ mBC from the tumor registry (from 2012-2021). Descriptive statistics were used to describe the demographic information and clinical characteristics. Kaplan-Meier method with log-rank test was used to analyze OS and PFS between both patient cohorts. Results 102 patients were identified that received trastuzumab or trastuzumab/pertuzumab for 5+ years. From this group, 33 patients were identified as NED based on clinical documentation and imaging. From our tumor registry data, there were 58 stage IV HER2+ patients. 34 patients met inclusion criteria for our non-NED cohort. The median follow-up time was 132 (range: 39 - 296) months for the NED cohort and 26 (range: 1-99) months for the non-NED cohort. The average diagnosis age was significantly older for the NED cohort (61 vs. 52 years, P=0.001). No other significant differences with respect to hormone receptor expression, race, or the presence of brain metastases were observed between groups. With respect to HER2 therapy, 61% of NED patients had received trastuzumab alone, and 39% trastuzumab/pertuzumab. By contrast in the non-NED cohort most received trastuzumab/pertuzumab (59%). The median time on HER2 therapy for the NED group was 125 months—70% of patients in the NED cohort were still receiving therapy vs, 12% for the non-NED cohort. As expected, the median OS (NR vs. 25.5 months; P< 0.0001) and PFS (NR vs. 7.9 months; P< 0.0001) were significantly longer in the NED cohort. 5 and 10 year OS rates for the NED cohort were 90.5% (95% confidence interval (CI): 80.8-100%) and 87% (95% CI: 75.9-99.8%), respectively. By contrast, for the non-NED cohort 5 and 10 year OS rates were only 21.3% (95% CI: 11.06-41.1%) and 0% (95% CI: 0-0%), respectively. 5 and 10 year PFS rates were 84.1% (95% CI: 72.2-97.9%) and 76.6% (95% CI: 67.7-93.6%), respectively for the NED cohort, and both were 0% for the non-NED cohort. The presence of brain metastases in the NED cohort was associated with reduced 5 and 10 year OS rates: 60% (95% CI: 29.3-100%) and 40% (95% CI: 13.7-100%), respectively. We observed in the NED cohort was associated with a drop in ejection fraction and clinically significant heart failure in 24% of patients while on HER2 therapy. Conclusions HER2+ mBC patients who achieve NED status have an excellent prognosis with starkly different clinical outcomes compared to HER2+ mBC patients who do not. We observed that 10 year OS rates in HER2+ NED patients was approximately 90%, which did not differ from 5 year OS rates. This suggests that HER2 therapy could be potentially discontinued after 5 years in mBC patients who achieve NED. More studies are needed to develop robust predictive markers for patients likely to achieve NED with HER2 targeted therapy. Citation Format: Alexis Bennett, Zhengyi Chen, James Martin, Naji Mallat, Pingfu Fu, Alberto Montero. Long term survival of metastatic HER2 positive breast cancer patients with no radiographic evidence of disease (NED) on HER2 antibody therapy [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 PO3-04-04.

Abstract PO5-07-01: A novel clinical risk score that can accurately predict the survival of young breast cancer patients: A UAE-based cohort study

Abstract Introduction: Breast cancer (BC) in women below the age of 40 accounts for approximately 7% of all BC cases. According to studies, BC in younger women is more likely to have negative tumor characteristics and outcomes compared to older women. The rate of early-onset breast cancer in the United Arab Emirates (UAE) is higher than in the Western population (24%, previously reported). Young breast cancer patients in the UAE have worse adverse features, including a higher grade, a larger tumor size, and lymph node involvement, as we reported previously. Therefore, combining several clinical indicators to predict recurrence risk in our unique, heterogeneous young breast cancer group is needed. Aim:The aim of this study is to develop a statistical machine learning model that can predict survival and the risk of recurrence in a young breast cancer population seen and treated in a large-volume tertiary cancer center in the United Arab Emirates (Tawam Hospital). Methods: Early-onset breast cancer patients from a retrospective observational cohort study were included in this study (N = 904). A broad range of clinical data was collected. A multivariate ridge Cox regression model was performed using age, histology, molecular type (ER,PR,HER-2 status), T-stage, N-Stage, M-stage, grade, and BMI, and the interaction term age*BMI at the time of diagnosis. The primary outcome was time-to-death. A novel breast cancer risk score (BCRS) was developed as the linear predictor of the fitted-ridge Cox regression model. Breast cancer patients were categorized into low, medium, and high risk using the 33th and 66th centiles of the novel BCRS. A univariate Cox regression model was performed with a categorized BCRS as a predictor of time-to-death. Hazard ratios (HR) with a 95% confidence interval (95% CI) were estimated. Kaplan-Meier (KM) curves were plotted and compared using the log-rank test. Time-dependent sensitivity and specificity were computed at five- and ten-year follow-ups, respectively. Statistical analyses were performed in R version 4.2.3. Results: The median age was 36 years (IQR: 32–38), and 64% were Arabic. Fifteen percent had an event with a median duration of follow-up of 15.4 years (95% CI: 13.6–17.1). The estimated HR of the categorized novel BCRS in a univariate Cox regression model was 1.968 (95% CI: 1.075- 3.601) and 8.040 (95% CI: 4.695–13.769) for the intermediate and high-risk groups as compared to the low-risk group, respectively. KM curves show a clear separation in terms of survival between the three risk groups, p< 0.0001 (Figure 1). A cutoff value of -1.733 gives a sensitivity of 93.8 and 90.6 with corresponding specificities of 31.42 and 31.31 at five- and ten-year follow-up, respectively. Conclusion: This is the first study in the region that uses clinical data that combines several clinical characteristics and aims to design a statistical machine learning model to predict the risk of death from breast cancer. Our novel model can be used in daily clinical practice to identify high risk breast cancer patients and aid clinical decision-making in patients with breast cancer. However, further validation studies are needed. Figure 1:KM curves of breast-cancer survival for patients with low-risk (BCRS in [-2.32, -1.63], black curve), intermediate-risk (BCRS in [-1.64, -1.25], red curve), and high-risk BCRS in [-1.26, 1.41], green curve). Citation Format: Aydah Al-Awadhi, Mohammed Hourani, Mawada Hussein, Fatima Alkindi, Lina Wahba, Abla AlAgha, Alaa Shoqeir, Mouza AlShebli, Atlal Abusanad, Amar Ahmad. A novel clinical risk score that can accurately predict the survival of young breast cancer patients: A UAE-based cohort 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 PO5-07-01.

Abstract PO1-18-11: Imaging of tumour microvasculature using high-resolution contrast enhanced ultrasound together with markers of proliferation/angiogenesis/vascular mimicry to characterise response to NACT in TNBC

Abstract Background: In the UK, triple-negative breast cancer (TNBC) comprises 10-15% of breast cancer diagnoses annually. TNBC represents a clinical challenge due to a lack of expression of three treatable drug targets, namely oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER-2). The mainstay of treatment involves the use of neoadjuvant chemotherapy (NACT) followed by surgical excision where up to 50% of patients will achieve a pathological complete response (pCR). The addition of neo-adjuvant immunotherapy may increase the pCR rate to 60%. The presence of lymphatics and blood vessels within/around malignant tumours plays a role in cancer progression as does the formation of new blood vessels (angiogenesis). The vascular endothelial growth factor (VEGF) family and their receptors (VEGFRs) play an important role in angiogenesis as well as promoting the growth and survival of cancer cells. VEGFR is frequently overexpressed in TNBC and promotes changes in vascular endothelial cells, the basement membrane and the surrounding extracellular matrix. Co-expression of epidermal growth factor receptor (EGFR) and VEGFR enhances tumour growth and angiogenesis in an autocrine and paracrine manner. An alternate mechanism for tumour microcirculation in tumours is vasculogenic mimicry (VM). This is distinct from classical tumour angiogenesis. The presence of VM is associated with poor overall survival in breast cancer patients and anti-angiogenic treatment of TNBC may even promote tumour growth, proliferation and metastasis by stimulating VM. Conventional imaging techniques such as B-mode ultrasound and MRI are commonly used to monitor disease response in the breast but have limited accuracy in predicting pCR or residual disease. High-resolution contrast-enhanced ultrasound (HRCEUS) may offer a more accurate test to monitor TNBC response to NACT. This method utilises intravenously injected microbubbles, which consist of a gas core with an outer shell of lipid/albumin to image tumour microvasculature as well as gross tumour morphology. Trial Design: Single-centre study to evaluate HRCEUS to image the microvasculature of TNBC tumours in patients undergoing (NACT) and correlate imaging results with established markers of angiogenesis, proliferation and vasculogenic mimicry. Eligibility Criteria: Female, 18 to 60 years, histologically confirmed invasive TNBC with planned NACT, able to consent and in the Investigator’s opinion, adhering to the trial recommendations and governance. Aims: To investigate if imaging changes in the tumour microvasculature indicate a response to NACT and are reflected in the expression of proliferative markers. To determine whether changes in the tumour microvasculature and disease response are driven by angiogenesis +/- VM. To investigate whether overall disease response and changes in the microvasculature are influenced by the basal type phenotype or germline mutations in BRCA 1/2. Investigate patient satisfaction with the contrast ultrasound test. Statistical Methods: Quantify HRCEUS imaging characteristics of microvasculature at 3 treatment points. Compare this with the results of conventional imaging and the histopathological results of surgical excision at the end of NACT. Quantify immunohistochemical markers of angiogenesis, proliferation and VM at three treatment points and compare this with HRCEUS. Determine phenotype of all cases using immunohistochemistry to identify the basal Perform subtype analysis to assess if the basal phenotype is associated with imaging and immunohistochemical changes in the microvasculature during NACT. Test patients for germline BRCA1/2 gene mutations. Perform subtype analysis to assess if germline BRCA1/2 mutations are associated with imaging and immunohistochemical changes in the microvasculature during NACT. Present accrual (2 patients) and target accrual (5 patients) Contact details: j.rait@nhs.net Citation Format: Jaideep Rait, Michelle Garrett, Catherine Harper-Wynne, Sonia Saw, Mengxing Tang, Priya Palanisamy, Matthieu TOULEMONDE, Karina Cox. Imaging of tumour microvasculature using high-resolution contrast enhanced ultrasound together with markers of proliferation/angiogenesis/vascular mimicry to characterise response to NACT in TNBC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-11.

Abstract PO5-23-08: Adenylosuccinate lyase is essential for proliferation and mitochondrial function of endocrine therapy resistant breast cancer cells

Abstract Eighty percent of breast cancers express estrogen receptor alpha (ERα, ESR1) at the time of diagnosis. Endocrine therapy (ET) is the standard treatment that either block estrogen mediated ER activation (such as tamoxifen, fulvestrant) or suppress estrogen synthesis (such as exemestane, letrozole, or anastrozole). While ET is initially effective, emergence of ET-resistance is common and possess a major clinical challenge. Hence, there is an ongoing need to develop new treatments for ET-resistant-ERα positive breast cancer. In this study we investigated the role of adenylosuccinate lyase (ADSL), an enzyme of the de-novo purine biosynthesis pathway as a potential target of ET-resistant breast cancer. The protein level of ADSL in two independent ET-resistant cell line model LCC9 and T47D-4HT cells were significantly higher in comparison to its parental ET-sensitive cell lines, MCF7 and T47D cells, respectively. Transient knockdown of ADSL using two independent siRNA in both LCC9 and T47D-4HT cells results in a significant decrease of cell growth, colony, and spheroid formation. Notably, reduced ADSL levels in LCC9 cells prevented the cells from progressing from G1 to S phase of cell cycle with concurrent elevation of cyclin D1/D3, CDK2/4, and cyclin E. On the other hand, in T47D-4HT cells, ADSL reduction caused cells to accumulate in S-phase of cell cycle and showed lower levels of total cyclin D1 protein. Mechanistically, in LCC9 cells (but not in T47D-4HT cells), ADSL depletion induced DNA replication stress which activates (phosphorylate) ataxia-telangiectasia-mutated-and-Rad3-related kinase (ATR) and its major downstream effector checkpoint kinase 1 (Chk1) that in turn failed to de-phosphorylate the inhibitory-phospho-groups of cyclin-dependent kinase 2 (CDK2). In addition, ADSL depletion perturbed the mitochondrial function in both LCC9 and T47D-4HT cells. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) was lower in both the cells along with the mitochondrial membrane potential. Pertinently, lower concentration of AICAR (5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside), a product of ADSL enzyme function, partially rescued the cell growth and restored mitochondrial membrane potential in ADSL-depleted LCC9 cells. To further understand the global effects of ADSL depletion we performed RNA-sequencing of LCC9 and T47D-4HT cells after ADSL depletion and compared with respective control siRNA transfected cells followed by gene set enrichment analysis. Intriguingly, diverse effect was observed in LCC9 and T47D-4HT cells as very few genes were found to be commonly regulated between these two cell lines. Analysis of clinical data sets revealed high level of ADSL transcript was associated with adverse progression free survival and overall survival in breast cancer patients treated with endocrine therapies. Overall, our findings demonstrate that ADSL-mediated de novo purine synthesis is critical for cellular growth, proliferation, and mitochondrial function of endocrine therapy-resistant breast cancer cells. Therefore, targeting ADSL is a novel potential therapeutic approach for ERα positive ET- resistant breast cancer. Citation Format: Anil Yadav, Lu Jin, Robert Clarke, Surojeet Sengupta. Adenylosuccinate lyase is essential for proliferation and mitochondrial function of endocrine therapy resistant breast cancer cells [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 PO5-23-08.

Abstract PO3-28-08: Triple Hormone Receptor Signatures as Novel Prognostic Markers in Breast Cancer

Abstract Background Tumor phenotype across various cancers, including breast cancer, is predominantly shaped by a synergy between genomic alterations and the cell-of-origin from which the tumor emerges. These elements collectively influence crucial aspects like tumor aggressiveness, treatment response, and patient prognosis. While existing research highlights that the cell-of-origin often leaves a lasting imprint on the molecular architecture of tumors, leveraging this information for actionable clinical insights has proven challenging. Specifically, in the realm of breast cancer, utilizing cellular ancestry signatures could be a key factor in tailoring effective therapeutic strategies and improving patient outcomes. Methods In this study, we developed a unique signature anchored in the expression levels of triple hormone receptors (THR)—namely androgen (AR), estrogen (ER), and vitamin D (VDR)—in normal breast cells. Building on this, we formulated two distinct mRNA markers, THR-50 and THR-70, aimed at categorizing breast tumors based on their THR expression profiles. These markers were rigorously validated across 65 independent breast cancer studies, involving a total of 6,679 patients, utilizing Kaplan-Meier survival curves, Cox proportional hazards models, and unsupervised clustering analyses. Results Our findings indicate that both THR-50 and THR-70 are robustly associated with overall survival and recurrence-free survival in breast cancer patients across all datasets evaluated. Importantly, these THR signatures demonstrate broad applicability across various breast cancer subtypes, grades, and treatment phases—unlike conventional prognostic markers that tend to be subtype-specific. Additionally, the THR signatures have revealed four unique patient clusters with divergent survival outcomes, three of which are ER-positive and one ER-negative. When augmented with an immune-based signature (i20), THR-70 identifies a specific ER-negative breast cancer subgroup with a highly favorable prognosis, comparable to ER-positive subtypes, as well as another ER-negative subgroup characterized by exceedingly poor survival outcomes. Conclusion The THR-based cellular ancestry signatures open a new avenue in understanding the intricacies of breast cancer biology. These signatures offer a robust and stable framework for developing other prognostic markers, thus providing an enhanced stratification of existing breast cancer categories as well as creating new classifications. Citation Format: Mohamed Omar, Chuck Harrell, Rulla Tamimi, Luigi Marchionni, Tan Ince. Triple Hormone Receptor Signatures as Novel Prognostic Markers 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 PO3-28-08.

Abstract PO1-25-03: Programmed Death-Ligand 1 and Receptor Tyrosine Kinases in Breast Cancer

Abstract Programmed death-ligand 1 (PD-L1) is an immune checkpoint expressed in a wide range of malignancies leading to immune tolerance and cancer cell immune evasion. Receptor tyrosine kinases (RTKs) are key regulators of cancer cell proliferation, survival, and invasion. The Hepatocyte Growth Factor (HGF) receptor, MET, and the Epidermal Growth Factor Receptor (EGFR) are RTKs known for their tumorigenic potential in a variety of human malignancies. This study aimed to evaluate the effect of the small-molecule tyrosine kinase inhibitors (TKIs) on the expression of PD-L1 in breast cancer cells and the effect of their combination with inflammatory cytokines. The study also assessed the association of the expression of the tumoral PD-L1 mRNA with each of MET and EGFR mRNA expression and the tumor features and treatment outcomes in breast cancer patients using the METABRIC dataset publicly available from cBioPortal for Cancer Genomics. The TKIs crizotinib [a MET inhibitor] and gefitinib [an EGFR inhibitor] were used as a single treatment and in combination with the cytokines; tumor necrosis factor-α (TNF-α) or interferon-γ (INF-γ) in MCF7 and MDA-MB-231 breast cancer cells in vitro. The cells were also treated with the mitogens HGF and EGF. The viability of cells after the different treatments was determined using the MTT viability assay. The effects of the combination treatments were analyzed using combination index (CI) analysis. The expression level of PD-L1 in cancer cells was assessed using Western blotting. The combination treatment of crizotinib with TNF-α and INF-γ produced a synergistic growth inhibition of MCF7 and MDA-MB-231 cells with CI values of 0.31 and 0.55, respectively. Alternatively, combined crizotinib and TNF-α produced an antagonist effect on the viability of MCF7 cells (CI=2.49). The combination of gefitinib with TNF-α produced a synergistic growth inhibition in both MCF7 and MDA-MB-231 cells with CI values of 0.39 and 0.78, respectively. Alternatively, gefitinib resulted in an additive effect when combined with INF-γ (CI=0.99) and an antagonistic effect when combined with TNF-α (CI=2.68) in MCF7 and MDA-MB-231 cells, respectively. Treatment with HGF (50 and 100 ng/ml) increased the protein levels of PD-L1 while EGF (50 and 100 ng/ml) reduced its levels in MDA-MB-231 cells. Treatment with the TKIs crizotinib (0.1-4 µM) and gefitinib (1-40 µM) significantly reduced PD-L1 levels in MDA-MB-231 cells compared to vehicle-treated cells. The analysis of the METABRIC dataset revealed that the mRNA expression of PD-L1 was positively correlated with the mRNA expression of the EGFR gene (r= 0.081, p< 0.001) but not the MET gene. A double-high PD-L1/MET expression was significantly associated with younger age at diagnosis, high-grade carcinoma, greater tumor size, hormone receptor-negative status, HER2-positivity, and non-luminal disease compared to patients with a double-low PD-L1/MET expression. Similar findings were reported for patients with a double-high PD-L1/EGFR expression compared to patients with a double-low PD-L1/EGFR expression. Nevertheless, the mRNA expression of the PD-L1, MET, and EGFR genes as well as the co-expression of PD-L1/MET or PD-L1/EGFR genes did not affect the overall survival of breast cancer patients. Collectively, MET and EGFR TKIs could modulate the effects of inflammatory cytokines differently based on the type of cytokine and the molecular subtype of breast cancer cells. The expression of PD-L1 in breast cancer cells was upregulated by HGF while TKIs reduced its expression. The co-expression of the PD-L1 gene with MET and EGFR genes in breast cancer was associated with advanced disease presentation and worse prognosticators in patients. Together, TKIs that target MET or EGFR could be an appealing therapeutic target in breast cancer, particularly in younger patients with the non-luminal disease. Citation Format: Nehad Ayoub, Muhsen Al-Diabat, Moath Al-Shorman, Laith Al-Eitan. Programmed Death-Ligand 1 and Receptor Tyrosine Kinases 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 PO1-25-03.

Abstract PO4-22-04: Evaluation of acute toxicity in breast cancer patients receiving concurrent capecitabine and radiation

Abstract Purpose: Adjuvant capecitabine has been shown to improve disease-free survival and overall survival in breast cancer patients who have residual disease after neoadjuvant chemotherapy, particularly in those with triple negative breast cancer (TNBC). While adjuvant chemotherapy is often completed prior to adjuvant radiotherapy (RT), capecitabine may be administered concurrent with RT to reduce the time from surgery to RT. The purpose of this study was to evaluate the feasibility of concurrent therapy and the associated rates of acute loco-regional toxicity. Materials and Methods: A retrospective chart review was performed to identify all breast cancer patients who received adjuvant capecitabine and RT. Patients with a history of prior RT, patients who were treated with capecitabine and RT sequentially, and patients who were treated with palliative intent were excluded. Capecitabine was given Monday-Friday during RT. Patient and disease characteristics, capecitabine and RT treatment details, acute toxicity, and treatment breaks were recorded. Toxicity was scored by the Common Terminology Criteria for Adverse Events (CTCAE) version 5. Results: A total of 27 patients with non-metastatic breast cancer who received concurrent capecitabine and RT with definitive intent treated from 2013 to 2023 were identified. Median age at diagnosis was 52 years [Interquartile Range (IQR) 40-60]. Adjuvant capecitabine dose ranged from 500-1500 mg twice daily. Adjuvant RT dose ranged from 42.56 Gray (Gy) to 50.4Gy. The majority of patients (92.6%) received a sequential 10-14 Gy boost to the lumpectomy site or mastectomy scar, and 70.3% of patients received elective regional nodal RT. During treatment, all patients developed Grade 1 or 2 radiation dermatitis, while Grade 3 radiation dermatitis was noted in 4 (14.8%) patients. Two patients required a treatment break from RT, and both patients were able to subsequently complete their planned RT course. Seven patients (25.9%) required a capecitabine dose reduction or capecitabine treatment break during RT. No Grade 4 or 5 toxicities were reported. Median follow-up from RT completion was 7 months [IQR 0.98-12.2]. At last follow-up, radiation dermatitis had improved to Grade 0-1 for all patients. Conclusion: Concurrent adjuvant capecitabine and RT is a feasible treatment approach that is well tolerated with acceptable acute toxicities. Citation Format: Ahmed Shalaby, Zohaib Sherwani, Lara Hathout, Imraan Jan, Bruce Haffty, Mridula George, Shicha Kumar, Coral Omene, Deborah Toppmeyer, Nisha Ohri. Evaluation of acute toxicity in breast cancer patients receiving concurrent capecitabine and radiation [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 PO4-22-04.

Abstract PO4-01-02: High throughput analysis in HER2 positive locally advanced breast cancer: pCR and mutational status

Abstract Background Pathologic complete response (pCR) after neoadjuvant treatment (NAD) is a strong prognostic biomarker associated with improved survival in breast cancer patients, especially with HER2-positive and Triple negative subtypes. PIK3CA is mutated in up to 20% of HER2 positive breast cancers, contributes to anti-HER-2 resistance and may be predictive of the lack of response to anti HER2 NAD. PIK3CA mutations in breast cancer occur primarily at hotspots E545K at exon 9 and H1047R at exon 20. Next generation sequencing has improved our knowledge regarding the biology of the mechanisms behind treatment resistance. The aim of this study is to evaluate the genomic landscape of tissue samples obtained from locally advanced breast cancer patients treated in an neoadjuvant setting, in order to correlate the genomic analysis to response and clinical outcome. Methods DNA extracted from the archival 84 formalin-fixed paraffin-embedded (FFPE) samples from core needle biopsies was subjected to deep sequencing using the TruSight Oncology (TSO) 500 panel (Illumina, San Diego, USA; 523 genes, size: 1.94 Mb), following the manufacturer’s protocol, which assesses microsatellite instability (MSI) status, tumor mutation burden (TMB), recurrent somatic copy number variations (sCNV), somatic single nucleotide variants (SNVs). Libraries were sequenced on a NovaSeq 6000 instrument (Illumina) to reach a minimum of 500 × read depth. All samples were evaluated for RNA single cell transcriptional profile. 73 of 84 patients were treated with traditional neoadjuvant chemotherapy plus trastuzumab meanwhile 13 of 84 received neoadjuvant chemotherapy plus trastuzumab and pertuzumab. Statistical analysis was performed to detect the genes whose mutation involved in the progression and/or non-response of the disease using the Statistical Package for Social Science (SPSS), release 23.0. Continuous variables were expressed as mean ± SD or median [range], categorical variables were displayed as frequencies and the appropriate parametric (Student‘s t-test) non-parametric test (X2-test or Mann-Whitney test) was used to assess significance of the differences between subgroups (patients with or without pCR). Results In total we analyzed samples of 84 patients. The median age was 48 years. 64 of 84 (76.2%) were triple positive, 66 (78.6%) with G3 and 29 (34.5%) with stage III. The most common frequently mutated genes were PIK3CA (16/84, 19%) and BRCA1 (7/84, 8.3%). The pathogenic variant of BRCA1 (sBRCA1) had a significant association with resistance to treatment: we found a pCR in only 14.3% of sBRCA1 versus 62.3% in sBRCA1 wild type (wt) patients (p=0.014). We also identified 11 somatic mutations in hereditary genes (ATM, BRCA1, BRCA2, PALB2, CHEK2, RAD51C, RAD51D). From a germline standpoint we detected 7 pathogenic variants (two affecting BRCA1, two affecting CHEK2, one affecting PALB2, 7/84, 8.3%), which will be clinically confirmed. Among patients with a mutated PI3KCA, 43.8% obtained a pCR versus 61.8% of patients with PI3KCA wt (p=0.19). This data probably presents an imbalance due to the sample size A PTEN mutation was identified in 2% of pts (2/84) which obtained no benefit in terms of pCR after NAD versus 59.8% in wt patients (p=0.09). Conclusions In this preliminary report, genetic drivers such as BRCA1 status may have a clinical implication for prognosis and treatment response after NAD in locally advanced HER2 positive breast cancer. More samples are needed to evaluate the significance of PI3K and PTEN mutations in this patient setting. We are waiting for the results of the RNA single cell transcriptional profile of these samples. Event free survival data is not yet mature at this moment. We would like to acknowledge the contribution of Multi-specialistic Biobank Research Core Facility G-STeP, Fondazione Policlinico Universitario “A. Gemelli” IRCCS (Biobank-FPG) who provided the bio-resources. Citation Format: Ida Paris, Angelo Minucci, Daniele Generali, simona Nanni, Tatiana D'angelo, Francesco Pavese, Alessandra Fabi, Maria De Bonis, Katia Cannita, Alessia Piermattei, Giordana Tiberi, Paola Fuso, Luisa Carbognin, Silvia Rotondaro, Camilla Nero, Flavia Giacomini, Tina Pasciuto, Maria Marrazzo, Luciano Giaco', Antonino Mulè, Riccardo Masetti, Gianluca Franceschini, Giorgia Garganese, Diana Giannarelli, Giovanni Scambia. High throughput analysis in HER2 positive locally advanced breast cancer: pCR and mutational status [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 PO4-01-02.

NREP, transcriptionally upregulated by HIF-1α, aggravates breast cancer cell growth and metastasis by promoting glycolysis

Breast cancer (BC) poses a great threat to women’s health. Neuronal regeneration related protein (NREP) is a multifunctional protein that is involved in embryonic development, regeneration, and human disease. However, the biological function of NREP in tumors is rarely reported and its role in BC remains unknown. Bioinformatics analysis showed that NREP is highly expressed and closely correlated with poor survival in BC patients. Under hypoxic conditions, NREP was upregulated in BC cells, and this promotion was reversed by hypoxia-inducible factor HIF-1α suppression. Luciferase reporter system and chromatin immunoprecipitation assays confirmed that HIF-1α directly binds to the promoter of NREP to increase the transcriptional activity of NREP. NREP suppression inhibited cell proliferation, arrested the cell cycle at the G1/S phase, and promoted apoptosis and caspase-3 activity in BC cells. Suppression of NREP decreased the tube formation ability of HUVECs. In addition, NREP downregulation showed an inhibition effect on cell migration, invasion, and EMT of BC cells. In NREP overexpressed cells, all these changes were reversed. In vivo, animal experiments also confirmed that NREP promotes BC tumor growth and metastasis. In addition, NREP promoted cellular glycolysis and enhanced the levels of glucose consumption, ATP, lactate production, and glucose transporters expression in NREP-overexpressed BC cells. In summary, our results demonstrated that NREP could be transcriptional activated by HIF-1α, which may aggravate BC tumor growth and metastasis by promoting cellular glycolysis. This result suggested that NREP may play an essential part in BC progression.

Abstract PS13-03: Safety of taxane chemotherapy for the treatment of breast cancer during pregnancy: an international cohort study

Abstract Introduction: The addition of taxanes to anthracycline-based chemotherapy regimens offers increased odds of survival in breast cancer (BC) patients. However, some clinicians defer their use in pregnant patients due to limited evidence supporting safety during gestation. The aim of this study is to describe the prevalence of maternal and neonatal adverse events in BC patients exposed to taxane-containing regimens during pregnancy. Methods: This is an international cohort study of BC patients treated with taxane chemotherapy during pregnancy. Inclusion criteria were age ≥18 years, treatment in a participating center (n=10), and completion of pregnancy. Results: A total of 103 women with a median age of 34 years (range 21-44) were included, of whom the majority (91/101; 90.1%) were also exposed to anthracyclines. The median gestational age at initiation of any chemotherapy agent was 16 weeks (range 4-34), while that of taxanes was 28 weeks (range 12-37). Paclitaxel was the most frequently used taxane (100/103; 97.1%), most prescribed as an 80 mg/m2 weekly infusion. All cases were singleton pregnancies except for one twin gestation. The overall live birth rate was 98.0% (100/102). Median gestational age at delivery was 37 weeks (range 32 to 40), with 36/83 live births being preterm (gestational age of < 37 weeks; 43.4%). Median birth weight was 2700 grams (range 1440-4000). The prevalence of grade 3 to 4 adverse events, obstetric complications, and neonatal outcomes are shown in the Table. A total of 56/58 (96.6%) of neonates had a 5-minute Apgar score ≥7 and 14/88 (15.9%) were admitted to a neonatal intensive care unit. Follow-up beyond the neonatal period was available for 28 neonates (median 42 months, range 1-228), of which reported adverse events were: cardiac abnormality (n=1), speech disorder (n=1), renal disfunction (n=1), and femoral anteversion (n=1). Conclusion: The use of taxane-containing chemotherapy during pregnancy does not seem to increase the risk of obstetric and neonatal complications. Our findings support the use of taxanes during gestation when clinically indicated. Table 1. Reported adverse events with gestational use of taxane-containing chemotherapy regimens. Citation Format: Ana Ferrigno Guajardo, Bryan Vaca-Cartagena, Erica Mayer, Chayma Bousrih, Oluchi Oke, Cristina Saura, Fedro Alessandro Peccatori, Wendy Muñoz-Montaño, Alvaro Cabrera-Garcia, Matteo Lambertini, Luis Corrales, Andrea Becerril-Gaitan, Tal Sella, Alexandra Newman, Barbara Pistilli, Ashley Martinez, Carolina Ortiz, Laia Joval-Ramentol, Giovanna Scarfone, Barbara Buonomo, Fernando Lara-Medina, Jacqueline Sanchez, Luca Arecco, Allan Ramos-Esquivel, Snezana Susnjar, Gilberto Morgan, Cynthia Villarreal-Garza, Hatem Azim. Safety of taxane chemotherapy for the treatment of breast cancer during pregnancy: an international cohort 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 PS13-03.

Abstract PO3-10-07: Leveraging AI to identify factors influencing access to care and their association with overall survival- a multiracial Breast Cancer cohort

Abstract Introduction: Data from the Centers for Disease Control and Prevention (CDC) labels each US state based on its 5-Year Relative Survival of Breast Cancer (BC) patients (pts). Data is categorized into four “survival groups'', each representing a range of 5-year survival percentages. Using real-world data, this study characterized the populations in each survival group, examining pt knowledge and education about their disease as well as preferences and factors influencing their decision to explore clinical trial (CT) opportunities. Methods: Leal is an AI-based platform that employs self-reported medical profiles to match cancer pts with CTs. This study involved a diverse cohort of 14,509 BC pts who completed the questionnaire. The geographic distribution of pts across US states was analyzed, taking into account the state’s 5-year BC survival %. Four groups were defined as follows: Group A (86.4 - 89.4%), Group B (89.4 - 90.4%), Group C (90.4 - 91.5%), and Group D (92.0 - 95.0%). Parameters such as race, willingness to travel, insurance coverage, performance of genetic testing, and biomarker knowledge were considered in the analysis. Results: We found significant variations in registration rates on the Leal platform across groups. The Highest registration rate was recorded for Group D which has the highest 5-year survival rate (p< 0.0001). Group A which has the lowest 5-year relative survival had a significantly higher proportion of African Americans compared to group D (14% vs 4%, p < 0.0001). Moreover, while there was no difference in the percentage of pts undergoing Next-Generation Sequencing (NGS) in both groups, a larger proportion of pts in Group D demonstrated proficiency in interpreting the test reports (p = 0.05). Although no significant differences were found in the proportion of pts who were aware of their treatment (tx) history between the two groups, whites in both groups exhibited greater knowledge of their tx (p = 0.001). Additionally, pts in Group D showed a significantly higher willingness to travel longer distances to participate in CTs (p=0.001), and a larger percentage of them had insurance coverage. Conclusions: This study used data from CDC that categorized US states into four groups based on BC pts’ 5-Year Survival. CT participation is associated with better clinical outcomes, especially for pts with poorer prognosis. In agreement, we show a higher signup rate to the Leal platform in States with higher 5-year relative survival, possibly pointing to higher CT education and knowledge among pts in those states. This is further supported by higher proficiency in interpreting NGS reports, resulting in better-optimized CT options on the Leal platform. Group A was also characterized by a reduced willingness to travel for a CT and a larger proportion of pts without health insurance. Those are significant barriers for CT enrollment, and ultimately limit access to optimal care and may impact outcomes. Gaps in knowledge of key disease parameters such as tx history were observed for African Americans, regardless of geographic location, highlighting the need to focus on minority populations even in states where the survival rate is relatively high. In agreement, the proportion of African Americans in group A was markedly higher, correlating with current disparities in access to tx and poorer outcomes. AI-based platforms are optimized for the exact identification of barriers to access to care and for enabling relevant healthcare and support organizations to effectively address individual patient issues, consequently increasing access to CTs, particularly among different racial and ethnic populations. Citation Format: Michal Safran, Yelena Lapidot, Tzvia Bader, Avital Gaziel. Leveraging AI to identify factors influencing access to care and their association with overall survival- a multiracial Breast Cancer cohort [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 PO3-10-07.

Abstract PO5-17-09: Event-free survival in HER2-low vs HER2-zero breast cancer patients submitted to neoadjuvant chemotherapy

Abstract Background: Breast cancer (BC) with low expression of HER2 (HER2-low) might constitute a group of tumors with unique clinical and biological characteristics. However, the prognostic impact of HER2-low status vs HER2-zero in terms of pathological complete response (pCR) and event-free survival (EFS) after neoadjuvant chemotherapy (NACT) remains controversial. The aim of this study was to evaluate pCR and EFS rates in HER2-low vs HER2-zero early BC patients treated with NACT. Methods: In this cross-sectional study, we analyzed 565 consecutive patients with HER2-low and HER2-zero early BC submitted to neoadjuvant therapy from 2017 to 2021 in a single academic center. Patients with biopsy-confirmed stage I-III BC, with HER2-low or HER2-zero status, submitted to locoregional therapy after NACT were included. Clinical and pathological characteristics, pathological response, treatment protocol and RFS were analyzed and considered for statistical analysis. HER2-low was defined by IHC 1+, or 2+ ISH non-amplified; HER2-zero was defined by IHC 0. Pathological response was determined locally, and pCR defined as the absence of residual invasive disease with or without ductal carcinoma in situ in the breast and axilla. EFS was defined as the time from diagnosis to distant recurrence, a second primary, or death from any cause, whichever occurred first. Results: 441 patients were included in the analysis, 236 (53.5%) patients with HER2-low tumors, and 205 (46.5%) with HER2-zero tumors. Overall, 279 (63.3%) were estrogen receptor (ER)-positive tumors, and 162 (36.5%) were ER-negative tumors. Among ER-positive tumors, 166 (59.5%) had HER2-low status, and 113 (40.5%) were HER2-zero. For the ER-negative subgroup, the corresponding rates were 70 (43.2%) and 92 (56.8%), respectively. Most patients had stage II-III BC (423/441; 96%), and 20.2% (89/441) had high nodal tumor burden. Many patients received anthracycline- and taxane-based NACT (425/441; 96.4%), and over 90% (148/162; 91.3%) of ER-negative patients received a platinum agent. The overall pCR rate were 18.1%. Among ER+ tumors, pCR rates were 6.4%, 6.0%, and 7.0% in the overall, HER2-low and HER2-zero tumors, respectively. In ER- tumors, the corresponding pCR rates were 38.3%, 35.7, and 40.2%, respectively. The differences in pCR rates between HER2-low and HER2-zero tumors were not statistically significant (ER-positive, p=0.724; ER-negative, p=0.559). After a median follow-up of 42 months, 90 EFS events occurred. In the HER2-low group there were 56 (23.7%) EFS events, and 34 (16.6%) EFS events in the HER2-zero (HR 1.19; 95% CI 0.77-1.82; p=0.427). Among 279 patients in the ER-positive group there were 48 events, 32 in the HER2-low subgroup and 16 in the HER2-zero group (HR 1.16; 95% CI 0.64-2.13; p=0.622). Among 162 ER-negative tumors there were 42 events, 24 in the HER2-low subgroup, and 24 in the HER2-zero subgroup (HR 1.56; 95% CI 0.84-2.88; p=0.158). NACT discontinuation occurred in 86 patients (ER-positive: 45, 16.1%; ER-negative: 41, 25.3%), mainly due to toxicity (anthracycline-taxane: 10.0%; platinum: 11.7%). Disease progression during NACT were reported in 6.8% (30/441) of patients. Conclusions: Our results show similar pCR rates and RFS among HER2-low and HER2-zero early BC patients after standard NACT, which are consistent with the current literature. Despite the predictive role of low HER2 expression in selecting patients for novel antibody-drug conjugates (ADCs) therapy, its prognostic value could not be confirmed. Citation Format: Guilherme Sartori, Susana Ramalho, Leonardo Roberto da Silva, Tomás Reinert, Mahira Lopes Da Rosa, Grazielle Morais Tavares, Vivian Vasconcelos, Higor Mantovani, Ana Elisa Ribeiro Da Silva Cabello, Guilherme Coelho, Jovana Mandelli, Facundo Zaffaroni, César Cabello, Carlos Barrios, Marcia Silveira Graudenz. Event-free survival in HER2-low vs HER2-zero breast cancer patients submitted to 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 PO5-17-09.

Abstract PO5-02-14: Clinical-pathological determinant factors to choose between four or six cycles of adjuvant chemotherapy with docetaxel/cyclophosphamide (TC) in a retrospective real-world cohort of HER2-negative breast cancer patients

Abstract Introduction: The long-term severe adverse events associated with anthracyclines, including irreversible cardiotoxicity, myelodysplastic syndromes, and therapy-related leukemias, led researchers to question the risk-benefit of anthracycline-based chemotherapy regimens, especially for patients without axillary lymph node involvement, leading to an increasing trend to omit anthracyclines in adjuvant treatment. Docetaxel plus cyclophosphamide (TC) has replaced doxorubicin plus cyclophosphamide (AC) for lower-risk patients that need adjuvant chemotherapy. However, the optimal number of cycles of adjuvant in patients with node-positive or node-negative breast cancer is currently unknown. Methods: We performed a retrospective cohort study of patients with HER2-negative breast cancer, stage I to III, that received adjuvant docetaxel and cyclophosphamide (TC) for four or six cycles, treated from January 2010 to December 2021. Patients were included from four cancer institutions, both private and public, located in the South, Southeast, and Northeast of Brazil. Objectives: To investigate the clinical-pathological characteristics and survival of earlystage HER2-negative breast cancer patients who received four (TC4) or six cycles (TC6) of adjuvant docetaxel and cyclophosphamide (TC). Results: We collected data from six hundred and ninety-eight patients, 98.7% were female with an average age of 52 years, 51.9% were postmenopausal, 14.6% BRCA gene mutation, 66% had some comorbidity, and only 8.4% were not candidates for anthracyclines. Two hundred and twenty-five patients had public and 473 private health insurance. About 13.2% of the patients were hormone receptor negative (HR-) and 86.8% hormone receptor positive (HR+), 57.4% breast-conserving surgery and 77.7% sentinel lymph node (SL). Five hundred sixty-four (80.8%) patients received TC4 and 134 (19.2%) TC6. We observed that patients who received TC 6 had unfavorable prognostic factors such as: (TC4 vs TC6) previous breast cancer (8.7% vs 16.3%) (p=0.002), invasive ductal carcinoma (IDC) (73.4 vs 86.7%) (p=0.009), histological grade 3 (HG3) (34.9 vs 42.9%) (p= 0,085) conservative surgery (59.4% vs 53%) (p=0144), SL (80.9% vs 62.2%) (p =0.001), Lymph node positive (15% vs 42.3%) (p=0.001), pathological stage II (37.5% vs 50%) (p=0.001).Treatment completion rates were 96.5% and 84.3% for TC4 and TC6, respectively (p=0,02). The incidence of grade 3 or higher toxicity with TC6 (14% vs 21.1%; p= 0,043). Febrile neutropenia was observed in 6.7% of both groups. Grade 3 or higher neuropathy was most common with TC6 (2.2% vs 10.3%; p=0,163). Permanent treatment discontinuation was more frequent in the TC6 group (3.4% vs. 9.8%; p=0,004), as well as late toxicity (3.4% vs. 9.2%; p=0,004). Ninety-four percent of the patients completed the proposed cycles of chemotherapy, 72% received adjuvant radiotherapy and 85.4% received adjuvant hormone therapy, with 42% of these receiving an aromatase inhibitor for 5 years. The median follow-up of the entire cohort was 61 months. There was no difference in the 5-year DFS (77.5% vs. 64.7%; p=0.159) or the 5-year OS (89.5% vs. 70.5%; p= 0,06) between patients treated with TC4 and TC6. Conclusion: TC6 was commonly used for patients with unfavorable prognostic factors as history of previous breast cancer, (IDC), HG III, lymph node positive and stage II. Patients who received TC6 had less chance of completing the treatment and more severe toxicity, especially late peripheral neuropathy. There was no difference in DFS or OS. Citation Format: Mila Kraychete, Marcelle Cesca, Guilherme Almeida, Leonardo Santana, Luciana Leite, Solange M. Sanches, Vladmir Cordeiro de Lima, Rafaela Pirolli, Rafael Manea, Felipe Kaneta, Jean Coutinho, Lucas Vian, Waires Zeviani, Marcio Reis, Luciana Landeiro, Clarissa Mathias, Geila Nunez, Tamara Santana, Monique Tavares. Clinical-pathological determinant factors to choose between four or six cycles of adjuvant chemotherapy with docetaxel/cyclophosphamide (TC) in a retrospective real-world cohort of HER2-negative breast cancer patients [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 PO5-02-14.

Abstract PO2-01-02: Clinicopathologic features and prognosis of breast cancer with low HER2 expression evaluated by fluorescence in situ hybridization

Abstract Background Although trastuzumab deruxtecan has been found to improve progression-free survival and overall survival of HER2-low breast cancer patients in DESTINY Breast04 trial, the characteristics and prognostic value of low HER2 expression remains to be elucidated. In this study, we retrospectively examined the clinicopathologic characteristics and prognosis of HER2-low expressing breast cancer. Methods A prospective database of 1026 clinical stage I to Ⅲ, HER2 negative breast cancer patients who underwent surgery from September 2012 to October 2022 at Teikyo University Hospital was analyzed. HER2 was evaluated by fluorescence in situ hybridization assay, and HER2-low and HER2-negative was defined as HER2/CEP17 ratio ≧1.0, and < 1.0, respectively. The chi-squared test was performed to estimate correlations between HER2-low status and clinicopathological factors. Distant-disease survival (DDFS) was calculated using the Kaplan-Meier curves and log-rank test. Multivariate logistic regression analyses were used to identify the independent prognostic factors. Results Median age, tumor size and ki67 of the entire 1026 patients was 56.0 years (range=23.0-93.0), 2.0 cm (range=0.3-15.0 cm), and 15.0 % (range=0.5-99.0 %), respectively. 155 (15.1 %) patients had lymph node metastasis. 904 (88.1 %) patients revealed hormone receptor positive (estrogen receptor [ER] positive; 904 patients, progesterone receptor [PgR] positive; 810 patients). Neoadjuvant and adjuvant chemotherapy was performed in 197 (19.2 %) and 160 (15.6 %) patients, respectively. Among all patients, 904 (88.1 %) patients had HER2-low tumors and 122 (11.9 %) patients had HER2-negative tumors. Positive rate of ER and PgR was significantly higher in HER2-low compared to HER2-negative patients (ER: 804 [88.9 %] patients vs 100 [82.0 %] patients; p=0.026 , PgR: 723 [80.0 %] patients vs 87 [71.3 %] patients; p=0.028). The median ki67 was significantly lower in HER2-low compared to HER2-negative patients (14.5 % vs 18.5 %, p=0.013). Pathologic complete response rates were not significantly different between HER2-low and HER2-negative patients (16.1 % [27/168 patients] vs 17.2 % [5/24 patients], p=0.528). With a median follow-up time of 39.7 months, DDFS was significantly better in HER2-low compared to HER2-negative patients (96.6 % vs 90.7 %, p=0.027). Multivariate logistic regression analyses showed that HER2-low expression was not independently related factors for DDFS. Conclusion These data suggested that HER2-low expression might not have significant association with prognosis despite significant correlation with ki67 and hormone receptor expression. Citation Format: Ayana Sato, Saki Naruse, Yuka Isono, Yuka Maeda, Miki Yamada, Akiko Matsumoto, Tatsuhiko Ikeda, Hiromitsu Jinno. Clinicopathologic features and prognosis of breast cancer with low HER2 expression evaluated by fluorescence in situ hybridization [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 PO2-01-02.

Abstract PO2-24-12: Tumor-specific circRNAs elicit anti-tumor immune response via encoding cryptic antigenic peptides

Abstract Emerging data have shown that previously defined noncoding genomes might encode human leukocyte antigen (HLA) binding peptides as cryptic antigens to stimulate adaptive immunity. However, the significance and mechanisms of cryptic antigens in anti-tumor immunity remain unclear. Here, mass spectrometry for HLA class I (HLA-I) peptidome coupled with ribosome sequencing of human breast cancer samples identified HLA-I binding cryptic antigenic peptides, which were noncanonically translated by a tumor-specific circular RNA CEIP (circCEIP). Importantly, the cryptic peptides efficiently primed naive CD4+ and CD8+ T cells in an antigen-specific manner and elicited anti-tumor immunity. Clinically, the expression of circCEIP and its encoding peptides was associated with massive infiltration of antigen-specific CD8+ T cells and better survival of breast cancer and melanoma patients. Mechanistically, circCEIP-encoding peptides had strong binding affinity to both HLA-I and II molecules, respectively. In vivo, administration of vaccines devised by tumor-specific circRNA or its encoding peptides in breast cancer or melanoma-bearing mice dramatically enhanced the infiltration of tumor-antigen specific cytotoxic T cells, leading to effective tumor control. Overall, our findings revealed that noncanonical translation of circRNAs can drive efficient anti-tumor immunity, suggesting that vaccination exploiting tumor-specific circRNAs may serve as an appealing immunotherapeutic strategy against malignant tumors. Citation Format: Di Huang, Jianing Chen, Shicheng Su, Erwei Song. Tumor-specific circRNAs elicit anti-tumor immune response via encoding cryptic antigenic peptides [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 PO2-24-12.

Impact of obesity on sentinel lymph node biopsy outcomes and survival in breast cancer patients: A single-center retrospective study.

Sentinel lymph node biopsy (SLNB) is a common choice for axillary surgery in patients with early-stage breast cancer (BC) who have clinically negative lymph nodes. Most research indicates that obesity is a prognostic factor for BC patients, but studies assessing its association with the rate of positive sentinel lymph nodes (SLN) and the prognosis of patients with early BC undergoing SLNB are limited. Between 2013 and 2016, 7062 early-stage BC patients from the Shanghai Cancer Center of Fudan University were included. Based on the Chinese Body Mass Index (BMI) classification standards, the patients were divided into three groups as follows: normal weight, overweight, and obese. Propensity score matching analysis was used to balance the baseline characteristics of the participants. Logistic regression analysis was used to determine the association between obesity and positive SLN rate. Cox regression analysis was used to investigate whether obesity was an independent prognostic factor for early-stage BC patients who had undergone SLNB. No significant association was observed between obesity and positive SLN rate in early-stage BC patients who had undergone SLNB. However, multivariate analysis revealed that compared to patients with normal BMI, the overall survival (hazard ratio (HR) 2.240, 95% confidence interval (CI) 1.27-3.95, p = 0.005) and disease-free survival (HR 1.750, 95% CI 1.16-2.62, p = 0.007) were poorer in patients with high BMI. Obesity is an independent prognostic factor for early-stage BC patients who undergo SLNB; however, it does not affect the positive SLN rate.

The therapeutic effect and targets of herba sarcandrae on breast cancer and the construction of a prognostic signature consisting of inflammation-related genes

BackgroundThe prevalence of breast cancer (BRCA), which is common among women, is on the rise. This study applied network pharmacology to explore the potential mechanism of action of herba sarcandrae in BRCA and construct a prognostic signature composed of inflammation-related genes. MethodsThe active ingredients of herba sarcandrae were screened using the SymMap, TCMID, and TCMSP platforms, and the molecular targets were determined in the UniProt database. The “drug-active compound-potential target” network was established with Cytoscape 3.7.2. The molecular targets were subjected to disease ontology, gene ontology (GO), and Kyoto Encyclopedia of Genes (KEGG) analyses. AutoDock software was used for molecular docking. Differentially expressed genes (DEGs) related to inflammation were obtained from the BRCA Cancer Genome Atlas (TCGA) database. In the training cohort, the univariate Cox regression model was applied to preliminarily screen prognostic genes. A multigene signature was built by the least absolute shrinkage and selection operator (LASSO) regression model, followed by validation through Kaplan‒Meier, Cox, and receiver operating characteristic (ROC) analyses. ResultsForty-one active compounds were identified, and 265 therapeutic targets for herba sarcandrae were predicted. GO enrichment results revealed significant enrichment of biological processes, such as response to xenobiotic stimuli, response to nutrient levels, and response to lipopolysaccharide. KEGG analysis revealed significant enrichment of pathways such as AGE-RAGE and chemical carcinogenesis receptor activation signaling pathways. In addition, the herbs Marc-Andre and rutin were shown to mediate BRCA cell proliferation and apoptosis via the interferon regulatory factor 1 (IRF1)/signal transducer and activator of transcription 3 (STAT3)/programmed death-ligand 1 (PD-L1) pathway. Sixteen inflammatory signatures, including BST2, GPR132, IL12B, IL18, IL1R1, IL2RB, IRF1, and others, were constructed, and the risk score was found to be a strong independent prognostic factor for overall survival in BRCA patients. The 16-inflammation signature was associated with several clinical features (age, clinical stage, T, and N classifications) and could reflect immune cell infiltration in tumor microenvironments with different immune cells. ConclusionsHerba sarcandrae and rutin were shown to mediate BRCA cell proliferation and apoptosis via the IRF1/STAT3/PD-L1 pathway, and the 16-member inflammatory signature might be a novel biomarker for predicting BRCA patient prognosis, providing more accurate guidance for clinical treatment prognosis evaluation and having important reference value for individualized treatment selection.