Triple-negative Cancer Research Articles

Ferrocenyl β-Diketonate Compounds: Extended Ring Systems for Improved Anticancer Activity.

A library of ferrocenyl β-diketonate compounds with varying degrees of aromatic functionality have been synthesized and fully characterized. This includes cyclic voltammetry and the analysis of four new structures by single crystal X-ray diffraction. The compounds cytotoxic potential has been determined by MTT screening against pancreatic carcinoma (MIA PaCa-2), ovarian adenocarcinoma (A2780), breast adenocarcinomas (MDA-MB-231 and MCF-7) and normal epithelial retinal (ARPE-19). The compounds show a general trend, where increasing the number of aromatic rings in the molecule yields an increase in cytotoxicity and follows the trend anthracenyl > naphthyl > phenyl > methyl. The compounds are particularly sensitive to the triple negative cancer cell line MDA-MB-231, and the potential modes of action have been studied by production of reactive oxygen species using fluorescence microscopy and cell morphology using Scanning Electron Microscopy. All assays highlight the ferrocenyl β-diketonate with an anthracenyl substituent to be the lead compound in this library. The decomposition was also observed within cells, to give a cytotoxic fluorescent molecule, which has been visualized by confocal microscopy.

Breast cancer statistics 2024.

This is the American Cancer Society's biennial update of statistics on breast cancer among women based on high-quality incidence and mortality data from the National Cancer Institute and the Centers for Disease Control and Prevention. Breast cancer incidence continued an upward trend, rising by 1% annually during 2012-2021, largely confined to localized-stage and hormone receptor-positive disease. A steeper increase in women younger than 50 years (1.4% annually) versus 50 years and older (0.7%) overall was only significant among White women. Asian American/Pacific Islander women had the fastest increase in both age groups (2.7% and 2.5% per year, respectively); consequently, young Asian American/Pacific Islander women had the second lowest rate in 2000 (57.4 per 100,000) but the highest rate in 2021 (86.3 per 100,000) alongside White women (86.4 per 100,000), surpassing Black women (81.5 per 100,000). In contrast, the overall breast cancer death rate continuously declined during 1989-2022 by 44% overall, translating to 517,900 fewer breast cancer deaths during thistime. However, not all women have experienced this progress; mortality remained unchanged since 1990 in American Indian/Alaska Native women, and Black women have 38% higher mortality than White women despite 5% lower incidence. Although the Black-White disparity partly reflects more triple-negative cancers, Black women have the lowest survival for every breast cancer subtype and stage except localized disease, with which they are 10% less likely to be diagnosed than White women (58% vs. 68%), highlighting disadvantages in social determinants of health. Progress against breast cancer could be accelerated by mitigating racial, ethnic, and social disparities through improved clinical trial representation and access to high-quality screening and treatment.

Prediction model for individualized precision surgery in breast cancer patients with complete response on MRI and residual calcifications on mammography after neoadjuvant chemotherapy.

Identifying whether there is residual carcinoma in remaining suspicious calcifications after neoadjuvant chemotherapy (NAC) in breast cancer patients can provide crucial information for surgeons in determining the most appropriate surgical approach. Therefore, we investigated factors predicting calcifications without residual carcinoma (ypCalc_0) or with residual carcinoma (ypCalc_ca) and aimed to develop a prediction model for patients exhibiting residual suspicious calcifications on mammography but complete response on MRI after NAC. This retrospective study included breast cancer patients undergoing NAC, showing residual suspicious mammographic calcifications but complete response on MRI between January 2019 and December 2020 (development set) and between January 2021 and December 2022 (validation set). Multivariable logistic regression analysis identified significant factors associated with ypCalc_0. The prediction model, developed using a decision tree and factors from logistic regression analysis, was validated in the validation set. The development set included 134 women (mean age, 50.6 years; 91 with ypCalc_0 and 43 with ypCalc_ca) and validation set included 146 women (mean age, 51.0 years; 108 with ypCalc_0 and 38 with ypCalc_ca). Molecular subtype (P = .0002) and high Ki-67 (P = .02) emerged as significant independent factors associated with ypCalc_0 in the development set. The prediction model, incorporating hormone receptor (HR)-/human epidermal growth factor receptor 2 (HER2)+ with high Ki-67 as ypCalc_0 predictors, and HR+/HER2- cancers or HR+/HER2+ or triple-negative (TN) cancers with low Ki-67, as ypCalc_ca predictors, achieved an area under receiver operating characteristic curve of 0.844 (95% CI 0.774-0.914) in the validation set. Minimized surgery may be considered for managing residual calcifications in HR-/HER2+ with high Ki-67 cancers, while complete excision is recommended for HR+/HER2- breast cancers or for HR+/HER2+or TN breast cancers with low Ki-67.

Impact of dynamic changes of tumor marker in neoadjuvant chemotherapy-treated triple-negative gastric cancer patients: a multi-center study

BackgroundIndependent and valid prognostic predictors for locally advanced gastric cancer (LAGC) patients with non-elevated serum tumor markers (Triple-negative: CA199 < 37U/ml, CEA < 5 µg/ml and CA125 < 35U/ml) before and after neoadjuvant chemotherapy (NACT) remain unclear.MethodsA total of 352 LAGC patients treated with NACT(NLAGC) from two centers were included. Of the 156 were Triple-negative patients. CA72-4 trajectory groupings was defined as longitudinal changes in CA72-4 levels before and after NACT to identify different potential subgroups and to compare recurrence-free survival (RFS) and overall survival (OS) among subgroups. The predictive performance of the nomogram-trajectory was evaluated using the area under the receiver operating characteristic curve(AUC), decision curve analysis, and C-index.ResultsIn the Triple-negative patients, the Stable group had significantly worse 3-year OS than the Normal, Elevated, and Descend groups(3-year OS: 53.9% vs. 77.9% vs. 73.5% vs. 87.7%;P = 0.002). Cox multivariate analysis showed that CA72-4 trajectory groupings (Stable group: HR:3.442, 95%CI[1.574–7.528], P = 0.002) was an independent prognostic risk factor. In addition, the C-index and AUC values based on the nomogram-trajectory were significantly higher than those of ypTNM staging (C-index: 0.788 vs. 0.719,P < 0.001;AUC: 0.800 vs. 0.667,P < 0.001). Furthermore, The survival analysis revealed that the 3-year OS of the Low-Risk group of nomogram scores was significantly better than that of the High-Risk group(3-year OS:84.7% vs. 29.1%). And the Low-Risk group had the lower cumulative risk of recurrence (P < 0.001).ConclusionThe CA72-4 trajectory groupings were an independent prognostic factor for NLAGC Triple-negative patients. The predictive efficacy of the Nomogram-trajectory was significantly better than the ypTNM.

Connexin 43 controls metastatic behavior in triple negative breast cancer through TGFβ1-Smad3-intergin αV signaling axis Based on optical image diagnosis

Abnormal expression of connexin 43 (Cx43) contributes to the development and progression of cancer. However, its regulation is complex and dependent on the environment. The expression of Cx43 in triple-negative cancer lesions was analyzed by immunohistochemistry and optical coherence tomography using experimental models and clinical samples. The model of TGFβ1-SMad3-in-αv signal axis was established and verified by experiments. The results show that Cx43 plays a key role in the regulation of triple-negative cancer metastasis. In vivo, over-expressed Cx43 decreased tumor volume and inhibited ITGαV, TGF-β1, Smad3 and N-cadherin expressions, but enhanced the E-cadherin. Cx43 had the lowest expression in the TNBC samples, especially in lymph node metastatic TNBC patients and had a negative correlation with ITG alpha V, TGF-β1 and Smad3.The study demonstrated Cx43 controlled metastatic behavior through TGF-β1 -Smad3-ITG αV signaling axis in MDA-MB-231 cells, providing evidence for Cx43’s function in TNBC. The optical image diagnosis method can realize the identification and quantitative evaluation of early cancer triple negative, and provide a new strategy and means for the treatment of cancer triple negative.

The Effect of Photobiomodulation on the Conditioned Media of 3T3-L1 Cells in the Treatment of Breast Cancer.

Introduction: Breast cancer ranks among the most prevalent malignancies, and its prompt diagnosis significantly amplifies the prospects of successful treatment. Approximately one in seven women will experience a breast cancer diagnosis in their lifetime. Stromal cells and their secreted factors exert various effects on tumor growth, impacting proliferation, invasion, and metastasis. Research has emphasized the significant impact of proteins secreted by adipose tissue on breast cancer proliferation, surpassing the influence of factors released by other cell types. Yet, the specific transcription factors and cofactors involved in adipokine expression in the tumor microenvironment remain enigmatic. Methods: In this study, adipocyte cells were cultured and exposed to 980 nm and 650 nm Photobiomodulation. The MDA-MD-231 cells (triple negative cancer cell line) were cultured with a conditioned medium from laser-treated cells. The real-time assay was employed to analyze the gene expression level changes involved in apoptosis. Results: Results showed that the irradiated conditioned medium at 980 nm and 650 nm caused a reduction in cell viability of cancer cells. Conversely, the conditioned medium from the irradiated cells triggered an increase in the expression of Caspase 3, Caspase 9, and BAX2 genes, alongside a decrease in BCL2 gene expression. Conclusion: The findings highlighted the potential of the laser-treated conditioned medium to induce apoptosis pathways in cancer cells, demonstrating a promising avenue for further research in utilizing low-level laser therapy in breast cancer treatment.

Tumor microenvironment activated and amplified self-luminescent nano photosensitizers for efficient treatment of triple negative breast cancer

Triple negative cancer (TNBC) is characterized as an aggressive phenotype lacking a specific therapeutic target. To date, self-illuminating photodynamic therapy (PDT) based on chemiluminescence resonance energy transfer (CRET) has emerged as a potential alternative for TNBC treatment by generating singlet oxygen (1O2), overcoming limitations in light penetration. However, this self-illuminating strategy heavily relies on endogenous hydrogen peroxide (H2O2) and oxygen (O2) within the tumor microenvironment (TME), resulting in inefficient therapeutic performance. In this study, we designed CLT@DPD nanoparticles capable of self-illumination via CRET and TME regulation through self-supplying H2O2 and O2. This nanoparticle was constructed by encapsulating luminol-tetreaphenylporphyrin conjugate (LT) and nanoscale CaO2 with DSPE-PEG 2000 and dioleoylphosphatidylcholine (DOPC). A good accumulation at tumor site was achieved due to enhanced permeability and retention (EPR) effect after intravenous injection of CLT@DP. Responsive to the high H2O2 levels and acidic aqueous conditions of TME, LT can be oxidized to produce 1O2via CRET, and the CaO2 can be decomposed to supply H2O2 and O2. Additionally, the presence of DOPC helps to enhance the permeability of the micelle shell under the oxidation of 1O2, thereby accelerating the release of H2O2 and O2. Our proposed nanoparticles exhibit excellent performance in eradicating in situ tumor cells and inhibiting metastasis by simultaneously enhancing self-luminous PDT and alleviating oxygen depletion in TME.

Clinical, Histopathological, and Immunohistochemical Characteristics of Predictive Biomarkers of Breast Cancer: A Retrospective Study.

Breast cancer is a complex disease with variability in clinical manifestation, response to current therapy, and biochemical and histological features among various subgroups. Histologic grading and immuno-histochemical evaluation of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 proliferation index play a crucial role in increasing the differential diagnostic value among various types of breast carcinoma. The aim of this study was to determine the histopathological and immuno-histochemical characteristics of breast tumors from a University Laboratory of Pathology in Greece. The study included female patients over 18 years of age, whose histopathological and immunohistochemical reports were stored in the archives of the First Department of Pathology of National and Kapodistrian University of Athens. The study involved 197 female patients with a median age of 70 years and median tumor size of 2.6 cm. Most tumors were located at the left breast and ductal carcinoma was the most common histologic type (35.5%). Most tumors had histologic grade 2 (106, 53.8%), and were classified as TNM stage IIA (65, 33%). Most grade 1 and 2 tumors exhibited high expression of PR, whereas most grade 3 tumors had no PR expression. Moreover, patients with triple-negative cancer presented with grades 2 and 3 at a lower percentage compared to patients without a triple-negative phenotype (p=0.001). The study provided valuable insights into the histopathological and immuno-histochemical characteristics involved in the development and progression of breast cancer.

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 PO3-02-09: Breast cancer in women under the age of 40 years.A south Wales UK reflection on incidence, tumour biology and outcomes over 10 years

Abstract Introduction: The incidence of breast cancer in the under 40-year-old age group is approximately 7% (Anders et al., 2009). Studies suggests that the management of Breast cancer in adolescent and young women is more challenging, with this age group under-represented in clinical trials. We investigated the management and outcomes of a cohort of 98 patients seen between 2013 and 2023 in the Hywel Dda NHS University Health Board, Wales, UK. Methods: A retrospective review was performed. Demographic, surgical and outcome data for patients under the age of 40 years was collated and analysed. Results: The cohort size was 98, representing 2.45% of the breast cancer population treated in the Health Board during this timeframe. The age of the cohort ranged from 23 years to 40 years, 12 out of 98 (12.24%) were under 30 years. Mean age was 35.28 years. Unfortunately, 8.16% (8/98) of the cohort died between 12 months to 96 months. Two patients were lost to follow up. Tumour biology results confirmed that most of the cohort had invasive ductal carcinoma (IDC), with 13.27% Grade 1, 37.76 % Grade 2 and 40.82% Grade 3. There were 4 (4.08%) invasive lobular carcinomas (ILC) in the cohort, 2 Grade 2 and 2 Grade 3. The remaining tumour groups were, 1 case of DCIS (Grade-2 intermediate grade), Grade-1 mucinous carcinoma, 1 Grade-1 ductal-lobular breast cancer and 1 medullary carcinoma. 10.20% of the cohort had triple negative cancers (ER, PR, Her-2 negative) and 10.20% were ER, PR, HER2 positive [Triple positive]. 40.82% metastatic axillary lymph nodes involvement on histology either on presentation or following sentinel node biopsy. Operative details confirmed that the 51.02% (50/98) of the cohort underwent mastectomy. 10 out of those 50 patients underwent contralateral risk reducing mastectomy .46 patients had breast conservation surgery. One patient is awaiting surgery, the other has been diagnosed with metastatic breast cancer at diagnosis. Patients received both neoadjuvant and adjuvant chemotherapy depending on initial assessment and MDT discussion [ACP, FEC, Taxane and platinum-based chemotherapy, Anti Her-2]. NAC was provided for all HER-2+ patients. Endocrine treatment and ovarian function suppression, and adjuvant Radiotherapy was also given. Some patients had a complete pathological response to NAC; however, some did not respond well. In addition, 10.20% of the cohort underwent bilateral salpingo-oophorectomy during their treatment and follow up. Genetic assessment confirmed that 3/98 (3.06%) of the cohort were BRCA2 positive, one BRCA1 carrier, 2 patients were BRCA negative, two have been referred for genetics assessment and two still awaiting consultation with genetics. In one patient somatic mutation was found in PTEN, BIRC3, HRAS, TP53, PMS, (5 gene panel). In one patient, panel was reassuring. PALB-2, TP53 was also reassuring in one patient. One patient who passed away at the age of 34 did not have any alteration in 5 gene panel. Three patients developed other malignancies during the 10-year period: 1 uterine, 1 cervix, 1 papillary thyroid cancer. 6/98 (6.12%) developed metastatic disease and one developed a local recurrence. One patient developed metastasis while pregnant, and by contrast one patient gave birth to a baby after stopping her endocrine treatment. One patient who passed away had no response to neoadjuvant chemotherapy (NAC). Discussion: The results from the cohort confirm that the incidence of TNBC and triple positive cancers is like that found in the general breast cancer population (10-15%). Our engagement with the genetics team has increased since the initial 2013 cohort. There is now an established system for referrals for young women with breast cancer. It is probably not surprising that other primary invasive cancers were found, whilst on follow up. Citation Format: Sohail Khan, Saira Khawaja, Yousef Sharaiha, Asma Munir, Anita Huws. Breast cancer in women under the age of 40 years.A south Wales UK reflection on incidence, tumour biology and outcomes over 10 years [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 PO3-02-09.

Abstract PO3-14-04: Prognostic value of systemic inflammatory markers in neoadjuvant chemotherapy for breast triple negative cancer with pembrolizumab: development of a nomogram

Abstract Introduction: Systemic inflammatory markers derived from peripheral blood cells, such as the neutrophil-lymphocyte ratio (NLR), derived neutrophil-lymphocyte ratio (dNLR), platelet-lymphocyte ratio (PLR), and lymphocyte-monocyte ratio (LMR), have shown promise as prognostic markers for various cancer types. Inflammation plays a crucial role in cancer development, progression, metastasis, and resistance to treatment. However, only a few preoperative biomarkers have been identified as independent prognostic markers. Systemic inflammatory markers offer a reliable and easily accessible approach for prognosis evaluation. Materials and Methods: This study evaluated two groups of patients who received neoadjuvant chemotherapy for triple-negative breast cancer outside of clinical trials. The first group underwent neoadjuvant chemotherapy in 2021 with the EC X4 and weekly paclitaxel regimen, whereas the second group received neoadjuvant chemotherapy in 2022 following the KEYNOTE-522 study protocol with pembrolizumab. A total of 44 patients were included, with 23 patients in the pembrolizumab group. The NLR was defined as the absolute blood neutrophil count divided by the absolute lymphocyte count, and the derived neutrophil/lymphocyte ratio (dNLR) was defined as the absolute neutrophil count divided by the derived lymphocyte count (absolute leukocyte count —neutrophil count). The PLR was defined as the absolute platelet count divided by the absolute lymphocyte count. The LMR was defined as the absolute lymphocyte count divided by the absolute monocyte count. The association between systemic inflammatory markers (NLR, dNLR, PLR, and LMR) and pathological complete response (pCR) was analyzed using statistical tests. Inflammatory markers were evaluated at the time of diagnosis, at the time of chemotherapy regimen change, and two weeks before surgery. The χ2 test or Fisher’s exact test was used to analyze the correlation between the inflammatory indices and clinicopathologic parameters. Student’s t-test was used to compare different groups of continuous parametric data. Results: The pCR rates were 67% in the standard therapy group and 87% in the pembrolizumab group. There were no significant differences in other clinical characteristics between the two groups. The NLR, dNLR, PLR, and LMR at 6 months showed statistically significant differences compared to baseline levels. This difference was more evident in patients undergoing pembrolizumab therapy. ROC curves for the pembrolizumab group demonstrated an area under the curve (AUC) of 0.737, indicating a strong correlation between these systemic inflammatory markers and pCR. Based on these data, a nomogram was constructed to predict the likelihood of achieving pCR in patients undergoing neoadjuvant pembrolizumab therapy. Conclusion: This study highlights the potential of systemic inflammatory markers as prognostic indicators in patients with TNBC undergoing neoadjuvant chemotherapy. The significant differences observed in the pembrolizumab group and the high AUC of the ROC curves suggest the utility of these markers in predicting treatment response. The developed nomogram provides a practical tool for clinicians to estimate the probability of pCR based on NLR, dNLR, PLR, and LMR. Further research and validation are required to confirm the clinical utility of these markers in larger patient cohorts. Nomogram –insert figure image– ROC curve –insert figure image– Citation Format: Filippo Giovanardi, Giancarlo Bisagni, Elisa Gasparini, Alessandra Bologna, Roberto Di Cicilia, Gabriella Moretti, Claudia Degli Esposti, Carmine Pinto. Prognostic value of systemic inflammatory markers in neoadjuvant chemotherapy for breast triple negative cancer with pembrolizumab: development of a nomogram [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 PO3-14-04.

Abstract PO2-29-04: An AI-based safeguard process to reduce aggressive missed cancers in dense breasts at screening mammography

Abstract Background: Dense breast tissue makes cancerous lesions difficult to identify on mammograms, resulting in many cancers missed at screening in patients with dense breasts. These missed cancers are then only diagnosed once they have grown to the point they can be more easily distinguished from the surrounding dense tissue. Dense breast tissue is more common in younger women, for whom early detection and diagnosis could lead to fewer years of life lost. This challenge motivated the FDA’s decision this year to require breast density to be included in patient reports, but notification does not solve the problem that these cancers are still often missed. Missing aggressive, fast growing cancers is particularly worrisome given they are more likely to progress to a stage where they are difficult to treat by the time they are detected in the future. Methods: A prospective study was conducted at one group practice of 6 radiologists over the course of 12 months to test a safeguard process to detect missed cancers so they could be treated more readily. AI software (Saige, DeepHealth, Inc.) was used to flag the most suspicious screening mammography exams that had not been recalled for work-up by an initial interpreting radiologist. An expert breast imager performed a safeguard review of each exam flagged. If the expert decided a recall was warranted, she would consult with the initial interpreting radiologist to decide if the patient should be recalled for further (diagnostic) imaging. Data was collected for each breast cancer diagnosed during this period. Patient data included breast density, age, and race. Cancer follow up data included pathology classification, hormone status, grade, staging, and Ki67 score. Aggressive cancers were identified as those with high grade (Grade 3), high Ki67 ( &amp;gt;=20%) or clinical stage of IIA or greater. A comparison was performed between cancers detected by the original interpreting radiologist and those detected through the safeguard process. Results: During the study period, 40,532 mammograms were obtained and 2,296 were flagged for safeguard review. The safeguard review led to 130 additional patient recalls and 41 additional cancer diagnoses. In women with dense breast tissue, 103 cancers were detected by routine interpretation and an additional 18 cancers (17.5%) detected through the safeguard process. In women without dense breast tissue, 116 cancers were detected by routine interpretation and 23 additional cancers were detected through the safeguard process. The cancers detected through the safeguard process included a larger percent of aggressive cancers (34.1% vs 30.6%, p=0.66) and more than double the percent of triple-negative cancers (9.8% vs 4.1%, p=0.13), though these differences were not statistically significant. The cancers detected through the safeguard process were from patients with similar demographics (age and race) to those whose cancers were detected by the interpreting radiologist. Conclusion: The AI-driven safeguard process results in a significant increase in breast cancers that would have been missed in patients with dense breast tissue. Many of the additional cancers were aggressive with almost 10% being triple-negative cancers. Without the safeguard process those aggressive cancers would not likely have been diagnosed until the next screening cycle in 1-2 years when treatment would likely have been less effective and outcomes poorer. Citation Format: Bryan Haslam, Jiye Kim, A. Gregory Soresen. An AI-based safeguard process to reduce aggressive missed cancers in dense breasts at screening mammography [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 PO2-29-04.

Abstract PS05-06: Outcomes of Surveillance using Contrast Enhanced Mammography in Women with a Personal History of Breast Cancer

Abstract Background Women with a personal history of breast cancer (PHBC) have a high rate of subsequent breast malignancy. Annual mammography with selective ultrasound has been the standard method of surveillance after breast cancer for many years, aiming for early detection, treatment and improved survival. In surveillance populations, interval cancers, which can account for ~30% of subsequent breast cancers, are more likely to be larger, hormone receptor negative and lymph node positive than cancers detected by surveillance (Lee et al, Radiology 2021). Interval cancer rates of 3.6 per 1000 mammographic screens have been reported previously in women with PHBC (Houssami et al, JAMA 2011). For women with PHBC a more sensitive surveillance approach may be justified, noting mammography has lower program sensitivity in PHBC surveillance than in screening. Magnetic resonance imaging (MRI) is used selectively but with resource and access limitations. Contrast enhanced mammography (CEM) offers a more sensitive modality than conventional mammography with specificity comparable to MRI, but its utility for surveillance is uncertain. Methods Retrospective study of 1,190 women with PHBC who commenced annual CEM surveillance in an Australian hospital setting between June 2016 and December 2022 (Elder et al, Breast Cancer Res Treat 2023) combining outcomes of initial CEM and any subsequent surveillance imaging over that period, including incident surveillance-detected cancers and interval cancers (cancers diagnosed in the year following a negative surveillance episode), recalls for assessment, the contribution of contrast to recall, and pathology and treatment details for cancer diagnoses. Outcomes were reported using descriptive statistics and hazards modelling. Results There were 3,784 episodes for analysis: 1,190 first CEM surveillance episodes, and 2,594 subsequent surveillance episodes of which &amp;gt;90% were contrast based imaging. 79% of women had at least three annual rounds of surveillance imaging. 186 cases from the total 3784 surveillance episodes were recalled for assessment (recall rate 4.9%). 72 (39%) recalled cases identified malignant lesions (true positives (TP)), with 50 invasive cancers and 22 cases of DCIS. 114 (61%) recalled cases were false positives (FP). 51% of cases were only recalled due to contrast and 35% of these were TP. Invasive cancers were predominantly stage 1 (64%) or stage 2 (32%) and most were grade 2 (44%) or grade 3 (47%). The median invasive cancer size was 16mm (IQR 9-25mm). 62% of invasive cancers were hormone receptor positive HER2 negative, and 24% were triple negative. The median DCIS size was 19mm (IQR 10-26mm) with only a single low grade case. 40% of invasive cancers and 59% of DCIS were recalled due to contrast. Comparison of tumour features indicates similarities between contrast-directed recalls and other diagnoses; conclusive findings would require a larger sample. Five interval cancers were identified, of which three were asymptomatic and detected on surveillance imaging scheduled early for other reasons. Thus, the rate of symptomatic interval cancers was 0.8 per 1000 screens (program sensitivity 96.0%). Surveillance-detected cancer rates differed significantly by index cancer subtype (χ2=11.9, p=0.0026), with highest rates for women with triple negative index cancers. Incidence cancer rates were higher among the 6.9% of women with moderate or marked BPE at first CEM surveillance episode (χ2=8.8, p=0.032), but did not differ significantly by age group (χ2=5.2, p=0.39) nor breast density (χ2=4.7, p=0.19). Conclusions Routine use of CEM in annual surveillance of women with PHBC led to 1.85-fold increase in the detection of clinically significant malignant lesions, with lower interval cancer rates than previous published series of women with PHBC. CEM appears to increase the sensitivity of surveillance programs for women with PHBC, improving on imaging without contrast. Citation Format: Julia Matheson, Carolyn Nickson, Kenneth Elder, Allan Park, Allison Rose, Bruce Mann. Outcomes of Surveillance using Contrast Enhanced Mammography in Women with a Personal History of Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS05-06.

Abstract PO3-20-10: Case Series: Invasive Secretory Carcinoma

Abstract Secretory variant invasive ductal carcinoma is not well described in the literature but is defined by its unique histopathology. These tumors stain positive for S100 and are typically triple negative hormonal cancers with an overall good prognosis. There is speculation that secretory carcinoma in adults is more aggressive with a greater likelihood for tumor recurrence. We present two case studies of this rare histopathologic diagnosis. First, a 76-year-old female with a recurrent secretory variant, invasive ductal carcinoma of the left breast. Second, a 68-year-old male who presented with invasive and in situ secretory carcinoma. A thorough chart review of all available institutional and outside institution records was performed from initial diagnosis to current treatment. Background information and de-identified patient information was summarized for this case series. This is a 76-year-old female who presented to her physician in 2011 with a palpable left breast and axillary mass. Her workup demonstrated ER+/PR+/HER2- invasive ductal carcinoma with lobular features of the left breast measuring 2.3 cm, along with a 1.5 cm malignant axillary lymph node. She underwent a left breast lumpectomy with axillary dissection. She underwent adjuvant whole breast radiation, axillary nodal radiation, and was placed on anastrozole therapy for 5 years. Seven years later a recurrence was noted in the superior aspect of the left breast. MRI guided biopsy revealed recurrent left breast cancer with pathology of invasive ductal carcinoma, secretory variant. She elected to undergo lumpectomy alone. Final pathology demonstrated invasive ductal carcinoma, secretory variant, ER negative (0%), PR negative (0%), HER2 negative (0%), pT1bNx. She underwent accelerated adjuvant partial breast radiation. Follow up and surveillance with bilateral breast MRI two years later demonstrated a new left breast mass, found to be triple negative, recurrent secretory variant invasive ductal carcinoma. She underwent definitive treatment with a left skin sparing mastectomy, right sentinel lymph node biopsy, and a latissimus dorsi flap with implant placement. Final pathology demonstrated multifocal recurrent secretory carcinoma, two foci measuring 6 and 11 mm. Our second patient was a 68-year-old male who initially presented to the clinic for evaluation of a ventral incisional hernia. During his initial assessment, a palpable retro-areolar nodule was noted on physical exam. Subsequent mammography demonstrated a hypoechoic mass with irregular margins measuring 2.8 x 2.3 x 1.7 cm along with increased vascularity and calcifications. An ultrasound guided biopsy demonstrated invasive secretory carcinoma. Initial pathologic testing of the tumor demonstrated ER positive (5%), PR positive (1%), and HER2 negative. The patient was taken to the operating room for a total mastectomy with sentinel lymph node biopsy. His postoperative pathology demonstrated negative margins, and invasive secretory carcinoma with lymph nodes negative for metastatic disease. Secretory variant of invasive ductal carcinoma is rare and is determined by its unique immunohistochemical features. We present two cases of secretory carcinoma at our institution. Data suggests that local recurrence is common in patients with secretory breast cancer, occurring in 33-44% of cases. Ki-67 index has been used as a prognostic indicator for metastases and recurrence of disease. Current treatment regimens are diverse; however, surgery is favored as the primary method. This report shows that although indolent, multifocality and recurrence is plausible. Given the limited data on this subset of carcinoma, more investigation is warranted to describe the effectiveness of adjuvant treatment options. Case 1 –insert figure image– Histopathologic examination at 200x shows invasive carcinoma with dense eosinophilic secretory material. By immunohistochemistry, the cells are negative for ER (0%) and PR (0%) with a HER2Neu score of 0, supporting the diagnosis of invasive secretory carcinoma. Case 2 –insert figure image– Histopathologic examination at 200x shows invasive carcinoma with dense eosinophilic secretory material. The tumor cells are positive for CK5/6 (patchy), CD117, ER (focal and weakly), and S100; negative for p63 and calponin, supporting the diagnosis of invasive secretory carcinoma. NTRK3 gene rearrangement was detected on fluorescence in situ hybridization (FISH). Citation Format: Lauren Geisel, Hemanth Venkatesh, Alyssa Obermiller, Quyen Chu, Jessica Gielow, Danielle Henry. Case Series: Invasive Secretory Carcinoma [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 PO3-20-10.

Abstract PO2-28-09: Long-term Breast Cancer Risk Prediction in Black Women: External Validation of a Mammography-driven AI Model

Abstract Despite the demonstrated potential of artificial intelligence (AI) in breast cancer risk assessment for personalizing screening recommendations, further validation is required regarding AI model bias and generalizability. We performed external validation in Black women of a mammography-driven AI breast cancer risk model (Mirai) originally developed on screening cohorts primarily consisting of White women. In this institutional review board-approved, Health Insurance Portability and Protection Act (HIPAA)-compliant study under a waiver of consent, we retrospectively analyzed a case–cohort sample nested within the core academic breast cancer screening practice of BJC Healthcare, the hospital partner of Washington University in St. Louis. For the purposes of this validation study, relying on 2D digital mammography (DM) images, we focused on Black women presenting for annual DM screening (Selenia or Selenia Dimensions; Hologic) between 2008 and 2018. Eligible breast cancer cases were derived from all women with a breast cancer diagnosis (with associated biopsy-confirmed tumor pathology via institutional cancer registry) after negative (BI-RADS 1 or 2) DM screening 1 to 5 years prior to cancer diagnosis. We also identified a random sample of controls, defined as women who had negative (BI-RADS 1 or 2) DM screening, with 1 to 5 years of screening follow-up without a cancer diagnosis. Risk scores for all DM exams were calculated via the Mirai model. Performance was evaluated using concordance-index (C) analyses and associated 95% confidence intervals (CIs) for the entire cohort, as well as for study subgroups of invasive versus in-situ cancer and cancer molecular subtypes. We analyzed 1368 DM screening exams, including 672 DM exams from 391 women diagnosed with breast cancer (mean age, 58 years; standard deviation, 10 years) and 696 DM exams from 406 controls (mean age, 55 years; standard deviation, 10 years). The overall C-index was 0.62 [95% CIs 0.60–0.64] for all Black women, which was lower compared to previously reported validation results for Mirai in studies of similar design on predominantly White and racially diverse screening cohorts (C-index = 0.67-0.78). There was no evidence of a significant difference between invasive and in-situ cancer (C-index = 0.64 [95% CIs 0.61–0.66] vs. 0.64 [95% CIs 0.61–0.67]). Compared to other cancer molecular subtypes, performance was significantly higher among triple-negative (C-index = 0.67 [95% CIs 0.62–0.71]) and estrogen receptor (ER) negative cancer (C-index = 0.66 [95% CIs 0.61–0.70]). A previously developed mammography-driven AI model showed overall good performance in long-term breast cancer risk assessment in a dataset of Black women only, particularly for triple-negative and ER- cancer types. However, performance was lower compared to previously reported validation results from similar studies on predominantly White and racially diverse screening cohorts. Our results suggest that further refinements are needed towards more accurate breast cancer risk assessment in Black women. Long-term breast cancer risk prediction performance (C-indices) of Mirai in the full cohort of Black women and in study subgroups. Citation Format: Juanita Hernandez Lopez, Zhixin Sun, Shirin Shoushtari, Ulugbek Kamilov, Debbie Bennett, Aimilia Gastounioti. Long-term Breast Cancer Risk Prediction in Black Women: External Validation of a Mammography-driven AI Model [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 PO2-28-09.

Abstract PO4-06-03: A comparative study between RECIST 1.1 using MRI and PERCIST 1.0 using PET/CT to evaluate the response in patients of carcinoma breast receiving neoadjuvant chemotherapy

Abstract Introduction: Breast cancer is the most common cancer in women leading to the major public health problem with an estimated new cases of 2,261,419 (11.7%). Depending upon the stage at presentation, the primary modalities vary. Presently, the primary option for HER2-positive, Triple negative cancers of size more than 2cm or nodal involvement and locally advanced breast cancer is neoadjuvant chemotherapy (NACT). Accurate assessment of the tumor response and residual cancer after undergoing NACT is considered crucial for reducing the number of local recurrence cases and to predict the prognosis as patients who achieve pathological complete response (pCR) after NACT have a longer disease free period and better overall survival as compared to non-responders. In our study we have compared the two commonly used criteria i.e. RECIST 1.0 and PERCIST 1.0. Methodology: 70 patients diagnosed with breast cancer requiring neoadjuvant chemotherapy were recruited in the study conducted in the department of surgical disciplines, AIIMS Delhi from January 2021 to December 2022. Each patient underwent a contrast enhanced MRI breast and whole body FDG PET/CT at the beginning of chemotherapy and after completion of chemotherapy within a stipuated time of two to three weeks. For RECIST 1.1 criteria, response assessment was done using MRI and PERCIST used PET/CT. The response was compared with the gold standard histopathological size. Results: Concordance between the RECIST 1.1 and PERCIST 1.0 response classifications was seen in 27 (39.1%) cases, while discordance was seen in 42 (60.8%). A significant difference was observed between RECIST 1.1 and PERCIST 1.0 (k=0.1309, p&amp;lt; 0.0001) for response classification. Tumor response was upgraded in 32 and downgraded in 2 patients using PERCIST 1.0 as compared to RECIST 1.1. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy to predict pCR along with comparison among different molecular subtypes is shown in the table below. Conclusion: RECIST 1.1 showed high specificity, PPV and accuracy in predicting pathological complete response but tends to underestimate it whereas PERCIST 1.0 showed higher sensitivity with a tendency to overestimate. RECIST 1.1 had a high level of specificity and NPV as compared to the PERCIST 1.0, which showed a high level of sensitivity and PPV. Thus, they act as complementary modalities for predicting pathological complete response. The accuracy to predict pCR was higher for the triple-negative phenotype and Her2 neu enriched with PERCIST 1.0 as compared to RECIST 1.1, while that of PERCIST 1.0 was lower for luminal type. Table. Comparison of RECIST 1.1 and PERCIST 1.0. Citation Format: Anita Dhar, Kanika Sharma. A comparative study between RECIST 1.1 using MRI and PERCIST 1.0 using PET/CT to evaluate the response in patients of carcinoma breast receiving 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 PO4-06-03.

Risk of first recurrence after treatment in a population-based cohort of young women with breast cancer

PurposeBreast cancer (BC) in women under 45 is rare yet often aggressive. We aim to analyze loco-regional recurrences (LR), distant recurrences (DR), second breast cancers, and mortality in young BC patients.MethodsWe enrolled 776 women with non-metastatic BC ≤45 years diagnosed from 1970 to 2012. Variables included age, family history, tumor stage/grade, and treatment. We used multivariate Cox regression and competing risk models.ResultsAmong the participants, 37.0% were diagnosed before the age of 40. Most had stage I or II, grade II, ER- and PR-positive, HER2-negative tumors. Over a median follow-up of 8.7 years, 10.1% experienced LR, 13.7% developed DR, and 10.8% died, primarily due to BC. The majority of recurrences occurred within the first five years. Older age (>40) significantly reduced the risk of LR and DR. Advanced disease stage, certain surgical strategies, and positive margins increased DR risk. In the cohort diagnosed between 2001 and 2012, recent diagnosis, triple-negative cancer, and hormonal therapy were associated with reduced LR risk. Breast-conserving surgery appeared to offer protective effects against DR.ConclusionThis study highlights that BC in young women carries a significant risk of early recurrence, with age, tumor characteristics, and treatment modalities influencing outcomes. The findings emphasize the need for tailored treatment strategies for young BC patients, focusing on surgical precision and aggressive adjuvant therapy for high-risk cases. This research contributes valuable insights into managing BC in younger patients, aiding in improving long-term outcomes.

Real-world data of HER2-negative early breast cancer patients treated with anthracycline and/or taxane regimens in Japan

BackgroundAnthracycline- and taxane-based chemotherapy regimens are established treatments for human epidermal growth factor receptor (HER)2-negative early-stage breast cancer with high risk of recurrence. This study examined the prevalence of these chemotherapy regimens as perioperative therapy, the patterns of retreatment, and factors influencing prescription choices in Japan.MethodsThis observational cohort study focused on high-risk early-stage breast cancer patients not undergoing anti-HER2 therapy, utilizing data from a hospital-based claims database in Japan spanning from April 2008 to September 2021.ResultsOf 42,636 high-risk patients who underwent breast cancer surgery, 32,133 (75.4%) were categorized as having luminal-type (received endocrine therapy) and 10,503 (24.6%) as having triple-negative cancer (not receiving any endocrine therapies). Most patients (98.7%) with luminal-type breast cancer received perioperative therapy, and 40.3% of those received anthracycline/taxane. In the triple-negative group, 57.0% of all patients received perioperative therapy and of those, 93.4% received anthracycline/taxane. Being over 40 years old, having an early stage (clinical stage ≤ II), and receiving treatment in non-specialized facilities were associated with less use of anthracycline/taxane in the luminal-type group. For the triple-negative group, associated factors with less use of anthracycline/taxane included being over 60 years old, treatment in small hospital (capacity < 200 beds), and treatment in non-specialized facilities.ConclusionsApproximately half the patients in both the luminal-type and triple-negative groups were prescribed anthracycline and/or taxane for perioperative chemotherapy. The choice was associated with patient age, cancer stage, and the scale and specialization of the treatment facilities. This study sheds light on the current state of breast cancer treatment practices in Japan.

Tissue Microarray Immunohistochemical Staining for Androgen Receptor in Breast Cancer in a Ghanaian Cohort.

Despite the advancement in therapy, breast cancer still remains the most common malignancy in women globally due in part to its heterogeneity. Triple-negative breast cancer (TNBC) represents up to 20% of all breast cancer variants, an aggressive disease with poorer outcomes compared to other breast cancer subtypes. No targeted therapies are currently approved for TNBC, and newer treatment approaches are seriously needed. Androgen receptor (AR), another hormonal receptor, is often expressed in breast cancer, and its role depends on the relative levels of circulating estrogens and androgens. This study aimed to assess the expression of AR in breast cancer in a tertiary hospital in Ghana. Immunohistochemical staining for AR was performed on tissue microarray (TMA) blocks, of which estrogen receptor, progesterone receptor, and Her-2/neu had already been done. 197 cases were suitable for the study. Results from the immunostaining were analyzed using the SPSS version 23 for descriptive statistics and correlations (χ2 and Pearson tests). 197 TMA cases were used. TNBCs constitute 61.9% of the cancers. The majority of these tumors were grade III, ductal carcinoma NST. The mean age was 49.86 ± 14.09, and the modal age group was 40-49 years. Our cases showed 23% AR expression in triple-negative cancers. The study also established that AR is more frequently expressed in low-grade tumors compared to high-grade ones. There is an appreciable level of AR expression in our cases; however, most are quadruple negative. However, AR is more frequently expressed in low-grade tumors than high-grade ones.

Abstract 7091: Significance of the tryptophan catabolism pathway in triple-negative breast cancer shows potential targets in certain subsets relating to the serine pathway

Abstract Background: Breast cancer (BC) is the most prevalent form of cancer worldwide, encompassing 12.5% of all forms of cancers with the fifth highest mortality rate. Triple negative cancers (TNBC), which account for 15~20% of BCs, are one of the most aggressive and heterogeneous forms of BCs, characterized by the loss of ER, PR, and low HER2 expression. This heterogeneity and plasticity are partly due to the adaptable nature of their metabolism, a dynamic phenotype which is commonly observed in many aggressive forms of cancer. One of the key metabolic pathways that can confer this aggressive proliferative characteristic is the tryptophan catabolism pathway. Tryptophan is an essential amino acid required for the proper function of all mammalian cells, with IDO1 being a key enzyme that converts tryptophan to kynurenine, marking the start of the catabolism pathway. IDO1 expression is observed to be elevated in various types of cancer including BCs and has been associated with immune suppression/evasion via resource competition and tumor progression by supplying resources required for proliferation. Despite this, tryptophan catabolism is one of the lesser studied and understood pathways in cancer metabolism, especially in the context of TNBCs. Methods: Previous analysis had shown the tryptophan catabolism pathway is downregulated in certain subsets of TNBCs. To understand the effective function of the pathway with regards to proliferation, we targeted the upper-most step of the catabolism pathway by inhibiting IDO1 with epacadostat and indoximod in different types of TNBC cell-lines and observed for changes in their growth rates via proliferation assays. We also performed parallel stable-isotope tracer-based flux analysis with [U-13C11]-Tryptophan and [U-13C3]-Serine with mass spectrometry to characterize flux changes with the goal of discovering potentially lethal metabolic pathways. Results: We observed higher proliferative sensitivity to IDO1 inhibition in TNBC cell-lines with a genetic dysfunction in the de novo serine synthesis pathway. To understand these differences at the metabolic level, we quantified the differential contributions of tryptophan and serine to nucleotide and NAD+ synthesis and the TCA cycle with the parallel tracer experiments. Comparison of the lines with dysfunctional de novo serine synthesis to those with normal or amplified flux towards the pathway showed a higher interdependence with the kynurenine pathway in the dysfunctional group. These results indicate a differential potential for targeting the kynurenine pathway in relation with the serine synthesis pathway. Conclusion: Targeting the IDO1 enzyme in the kynurenine pathway shows significant correlations between the de novo serine pathway and the tryptophan catabolism pathway in TNBCs that may lead to metabolic targets conferring potential therapeutic benefits. Citation Format: Jin Heon Jeon, Abhinav Achreja, Mark Slayton, Olamide Animasahun, Minal Nenwani, Miya Paserba, Zackariah Farah, Sofia D. Merajver, Deepak Nagrath. Significance of the tryptophan catabolism pathway in triple-negative breast cancer shows potential targets in certain subsets relating to the serine pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7091.