tbuckley/cabot-search huggingface dataset:
Spatial transcriptomic and proteomic insight into Trop-2, HER2, and AR expression: A pathway to tailored therapies in triple-negative breast cancer.
Authors: Marcela Carausu, Frédéric Lifrange, David Venet, Ghizlane Rouas, XiaoXiao Wang, Denis Larsimont, Françoise Rothé, Christos Sotiriou
Journal: Journal of Clinical Oncology (2024)

e12576 Background: Triple-negative breast cancer’s (TNBC) dismal prognosis demands more effective therapy selection. Previously described molecular subtypes reveal its heterogeneity but lack spatial insight and are not currently used in clinical practice. Here, we aim to evaluate by immunohistochemistry (IHC) the expression of key biomarkers in TNBC and its correlation with spatial gene expression obtained by spatial transcriptomics (ST). Methods: We studied a retrospective cohort of 92 patients (pts) treated at the Institut Jules Bordet in Belgium with primary surgery for early TNBC. ST (Visium Spatial Gene Expression, 10X Genomics) was previously performed on fresh frozen surgical samples. Using serial sections of these samples, we performed duplex IHC staining for Trop-2/androgen receptor (AR) and HER2/Ki-67. IHC staining was scored using H-score (Trop-2), Allred score (AR), and current guidelines (Ki67/HER2), adding the ultra-low and null HER2 categories. Statistical analyses included descriptive statistics, Spearman correlation, Mann-Whitney test, and Kaplan-Meier with log-rank tests for estimating outcome distribution. Results: Of 92 pts included, 4 (4.3%), 25 (27.2%), 28 (30.4%), and 35 (38%) pts had HER2 2+, 1+, ultra-low, and null, respectively, tumors. Importantly, we observed a significant difference in tumor cell-derived ERBB2 gene expression of HER2 ultra-low versus HER2 null tumors ( p&lt;0.0001), while there was no difference in ERBB2 expression between HER2 ultra-low and HER2 1+ tumors ( p=0.49). HER2 expression was not correlated with prognosis. Trop-2 expression by IHC was high, medium, and low in 67%, 23%, and 10% of pts, respectively. IHC expression correlated well with tumor-derived gene expression (r=0.54), with intrasample heterogeneity observed both in IHC and spatial gene expression. Trop-2 expression was prognostic, pts with high Trop-2 H-score tumors having significantly worse outcome ( p=0.021). In this cohort, 25%, 40.2%, and 34.8% of pts had AR Allred scores of 0-2, 3-5, and 6-8, respectively. Tumor AR gene expression was well correlated with IHC AR expression (67.7%). IHC AR expression was associated with the presence of adipose tissue in the stroma (r=0.23, p=0.025) but not with prognosis. Of note, we report for the first time, to our knowledge, for TNBC, AR expression both in tumor and stroma cells, both at the IHC and gene expression levels. Importantly, we could construct a classifier that identifies luminal androgen receptor tumors, using AR Allred score &gt; 5 and Ki67 ≤ 40%, with a PPV of 93% and an NPV of 96%. Conclusions: ST data has the potential to improve easily accessible IHC classifiers, with the aim of refining patient selection for ADC and anti-AR therapies in TNBC.
Impact of aromatase inhibitors on mortality and hospitalization costs in patients with breast cancer: A National Inpatient Sample analysis 2020.
Authors: Sripada Preetham Kasire, Maneeth Mylavarapu
Journal: Journal of Clinical Oncology (2024)

e13160 Background: Breast cancer is a significant public health concern globally, affecting millions of individuals each year. Aromatase inhibitors are a class of medications commonly used in the treatment of hormone receptor-positive breast cancer. The significance of the study lies in the impact of aromatase inhibitors on mortality and also healthcare-related costs for the treatment of breast cancer. Methods: The National Inpatient Sample database (2020) was used to identify adult patients with breast cancer using ICD-10 codes. Demographics (age, race, sex, region, and hospital size), co-morbidities, and hospitalization costs were compared between the two groups of patients: those who are on aromatase inhibitors and those who are not. The odds of mortality were analyzed. A p&lt;0.05 was considered statistically significant. Results: Out of 166870 patients who had breast cancer, 12975(7.7%) were on aromatase inhibitors. The aromatase inhibitors group was relatively older (median age, 69.4 years vs 64 years) and predominantly white (71.50% vs 66%) compared to the non-aromatase inhibitors group. The prevalence of heart failure and osteoporosis was greater in the aromatase inhibitors group than in the non-aromatase inhibitors group. The adjusted odds ratio of mortality in the aromatase inhibitors group was 0.45, 95% CI (0.39-0.50, p&lt;0.0001). Furthermore, the average total cost of hospitalization in the aromatase inhibitor group was $6426 less than the non-aromatase inhibitor group. Conclusions: Our study findings indicate that breast cancer patients treated with aromatase inhibitors experienced lower odds of mortality and lesser costs of hospitalization. However, the aromatase inhibitor group was found to have a higher prevalence of heart failure and osteoporosis. Hence, further research needs to be done on potential adverse effects and long-term effects of the aromatase inhibitors treatment.
Predicting locoregional recurrence in triple-negative breast cancer using novel molecular subtyping.
Authors: Shali Shao, Wei Shi, Li Zhang, Qixian Zhang, Jin Meng, Zhaozhi Yang, Xin Mei, Xingxing Chen, Jinli Ma, Miao Mo, Zhimin Shao, Zhen Zhang, Xiaomao Guo, XiaoLi Yu
Journal: Journal of Clinical Oncology (2024)

e12549 Background: Triple-negative breast cancer (TNBC) presents a poorer prognosis compared to other breast cancer subtypes, characterized by a higher likelihood of early recurrence and increased incidence of visceral metastases. Evidence from numerous randomized clinical trials indicates that postmastectomy radiotherapy (PMRT) reduces locoregional recurrence (LRR) and improves breast cancer survival in TNBC. Previous reports creatively divided TNBC into four molecular subtypes for personalized treatment. The present study aims to elucidate patterns of LRR in different subtypes of TNBC after PMRT. Methods: From 2019 to 2022, data from 349 AJCC 7th edition stage II-III breast cancer patients treated with mastectomy and PMRT were retrospectively analyzed. These patients were classified into the basal-like immune-suppressed (BLIS) and non-BLIS groups based on the immunohistochemistry biomarkers. The cumulative incidence function was applied to estimated LRR rates, with death as a competing risk, using Gray's test for comparisons. Results: According to the IHC results, a total of 255 patients belonged to the non-BLIS group and 94 to the BLIS group. The 3-year LRR for the entire cohort was 5.16%. There were 9 cases each in the non-BLIS subtype (3.5%) and BLIS subtype (9.6%). The cumulative incidence of LRR between the two groups was significantly different, with a rate of 4.0% in the non-BLIS group and 9.0% in the BLIS group ( P = 0.02). Among the 18 patients with LRR in the whole population, 11 had isolated LRR and 7 were diagnosed with LRR with concurrent distant metastases. The most common area of recurrence in both subtypes was the supraclavicular region. The majority of recurrences occurred within the RT field (in-field), and no isolated out-of-field relapse was observed. In multivariate analysis, independent factors predicting higher LRR were the BLIS subtype (HR = 3.06, P = 0.02). Conclusions: Study results suggest that TNBC of the BLIS subtype is at higher risk for LRR. Immunohistochemistry-based molecular typing may serve as a prognostic biomarker to guide postmastectomy radiotherapy in patients with TNBC. New strategies are needed to improve local control rates in patients with BLIS subtype.
Dose escalation and expansion results from the phase I study of F0024, a trophoblast cell-surface antigen 2 (TROP2) antibody-drug conjugate (ADC), in patients (pts) with advanced solid tumors.
Authors: Yiqun Du, Yanchun Meng, Jingfen Wang, Ying Wang, Fan Wu, Yu Chen, Lilin Chen, Lihua Qing, Yaya Qiao, Kezhen Liu, Wenyi Sun, Xiaowen Li, Jian Zhang
Journal: Journal of Clinical Oncology (2024)

e13131 Background: F0024 is an antibody-drug conjugate (ADC) targeting Trop-2, an intracellular calcium signaling transducer overexpressed on many epithelial tumors, for delivery of SN-38, the active metabolite of irinotecan. We assessed its safety and efficacy in patients with advanced solid tumors, mainly in triple negative breast cancer (TNBC). Methods: PTs with unresectable solid tumors refractory to/relapsed from standard treatment received F0024 on days 1 and 8 of 21-day treatment cycles. Primary objectives include maximum tolerated dose (MTD) identification, safety, and tolerability and secondary objectives include efficacy, pharmacokinetics, and incidence of anti-drug antibodies against F0024. Pts were eligible regardless of TROP2 level. Results: As of October 8, 2023, 62 pts were treated with≥1 dose of F0024. 21 pts were treated during dose escalation at 2.5 (n = 1), 5.0 (n = 3), 7.5 (n = 3), 10 (n = 4), 12 (n = 8), and 15 (n = 2) mg/kg and 41 pts with TNBC were treated in dose expansion at 10.0 (n = 30) and 12.0 (n = 11) mg/kg. 32 pts (51.6%) discontinued (20 (32.2%) due to disease progression per RECIST v1.1). Treatment emergent adverse events (TEAEs) regardless of causality were reported in 61 of 62 pts (98.4%; 34 pts [54.8%] experienced ≥grade 3, 9 pts [14.5%] had serious adverse events). Treatment related adverse events (TRAEs) were reported in 61 of 62 pts (98.4%; 32 pts [51.6%] experienced ≥grade 3, 4 pts [6.5%] had serious adverse events). The most common grade 3 TRAE were neutropenia (45.2%), leukopenia (33.9%), febrile neutropenia (4.8%), anemia (4.8%), and maculo-papular rash (4.8%). A total of 17 responses have been observed at the dose of 5.0 mg/kg or greater. 34 TNBC pts were dosed at 10 and 19 were dosed at 12 mg/kg with exposure to a median of 11.5 (1.0-26.0) and 4.0 (1.0-21.0) doses. 11 partial responses were achieved in 29 efficacy-evaluable TNBC pts at 10 mg/kg leading to an overall response rate (ORR) of 37.9% (95% CI 20.7% - 57.7%). The disease control rate of 10 mg/kg is 79.3% (95% CI 60.3%-92.0%). 5 escalation pts and 25 expansion pts remain on trial. Updated trial details/results will be presented. Conclusions: In this first-in-human study of F0024, treatment was generally well tolerated and MTD was not yet reached up to 12 mg/kg. F0024 demonstrated encouraging preliminary antitumor activity in heavily pretreated TNBC pts, especially in 10 and 12 mg/kg. Clinical trial information: NCT05174637 .
Everolimus for advanced breast cancer: Is the histological subtype important?
Authors: Alicia Vargas, Pablo Flores Paco, Juan De La Haba, Cristina Morales-Estevez, Beatriz Rodríguez-Alonso, Ignacio Porras, Luis de la Cruz-Merino, Clara Muñoz, Margarita Lorente, Encarnación González Flores, Pedro Sanchez-Rovira, Rafael Arenas, Ana Armenta, Enrique Aranda
Journal: Journal of Clinical Oncology (2024)

e13165 Background: Invasive lobular (L) breast carcinomas (BC), which account for up to 15% of all BC, had particularly histopathological characteristics: tends to be estrogen/progesterone receptor positive and HER2-neu negative and as such are treated with endocrine therapy (ET). It had been demonstrated a frequent activation of PI3K–AKT–mTOR signaling in LBCs, suggesting this pathway to be a promising therapeutic target for LBC. Interestingly, in some of these patients, the subsequent use of a mTOR inhibitor (everolimus) combined with an ET produced greater clinical benefits. Our aim is to evaluate the efficacy of everolimus in advanced BC (ABC) in the usual clinical practice, focusing on LBC. Methods: We retrospectively analyzed 147 women with ABC from four Spanish hospitals who were treated with everolimus (Ev) in second or successive lines of treatment between 2014-2023. We performed a descriptive statistical analysis of the clinicopathological variables and calculated the investigator-assessed time to treatment failure (TTF), defined as the interval from initiation of treatment to its premature discontinuation (because of progression disease (PD) or toxicity), as well as its association using Kaplan-Meier test. Survival curves were analyzed using long-rank test. Finally, we analyzed the subgroup of those with everolimus TTF (TTF2) longer than previous line TTF (TTF1) by Xi 2 test. Results: With a median (m) age of 59, 21 (14%) patients (pts) were diagnosed with advanced LBC. The histopathological characteristics of the pts are shown (Table). Treatment had to be stopped in 24 pts due to toxicity (oral mucositis 21%), and the rest was due to PD or exitus. The response rate (stabilization, partial and complete response (CR)) was 49% with 4% of CR. The overall m of TTF2 was 9,1 months, while the TTF1 m was 9,5 months. Analyzing by histology, TTF2 m was 18.16 months in LBC vs 7.85 in ductal BC (p=0.01). Contrary to expectations, 40 pts (27,2%) had a longer TTF2 compared with TTF1 (p&gt;0.001). When analyzing this subgroup we found 9 pts with LBC and 27 DBC (p&gt;0,05). 26 pts (65%) had not received previous line with HT (p=0.005). On the other hand, when analyzing the subgroup of pts with LBC, up to 47.36% of pts had TTF2&gt;TTF1. Conclusions: The use of everolimus in pts with LBC appears to be more effective than in DBC according to the results reported in our series and its use in initial hormonal lines may be reconsidered. However, we need more prospective studies differentiating histologies to demonstrate our results for others Pi3k inhibitors. [Table: see text]
Mutational landscape of HER-2 low breast cancer.
Authors: Elham Vosoughi, Nellie Nafissi, Aditya Mahadevan, Seungshin Lee, Rita S. Mehta, Ritesh Parajuli
Journal: Journal of Clinical Oncology (2024)

e13040 Background: HER2-low breast cancer is defined as HER2 IHC score of 1+ or 2+/ISH- tumors. Anti-Her-2 therapies such as trastuzumab deruxtecan improve progression-free survival (PFS) and overall survival (OS) in patients with HER-2 low metastatic breast cancer. However, the mutational landscape of HER2-low BC is still not well defined. The aim of this study is to characterize the biological and clinicopathological landscape of HER2-low BC by next generation sequencing. Methods: We conducted a single institution, retrospective chart review of patients with metastatic breast cancer (MBC) from 1/2020 to 4/2023. We obtained Next generation sequencing data and correlated it with clinical outcomes. Patients with HER2 IHC score of 1+ or 2+/ISH- tumors referred as HER2-low, while with no HER2 IHC staining at all were referred as HER2-zero, and pts with HER2 IHC 3+ or HER2 IHC 2+/ISH+ referred as HER2+. Results: A total of 98 pts were enrolled:45 pts with HER2-low tumors, 29 pts with HER2+ and 24 pts with HER2-zero tumors. In the HER2-low cohort, 58% (26 pts) were initially diagnosed with loco regional disease while 42% presented with stage IV at diagnosis. On average patients were on 3 lines of therapy for metastatic disease (ranging between 1 to 12). Of those 35% received T-DXd. High Ki-67 proliferation (≥20), reported in 58% (26 pts). OS was 54.4 months, 95% CI [ 42.5,100.2]. In the HER2+ cohort, 31% of pts presented with stage IV at diagnosis. On average pts received 3 lines of therapy (ranging from 1 to 14). 69% of pts received T-DXd. High Ki-67 reported in 48% of pts. OS was 59.2 months, 95% CI [39.2,96,1]. In the HER2-zero, 62.5% of pts presented with stage IV. On average pts received 1 line of therapy (ranging between 1 to 5), 62% of pts had high Ki-67. OS of 41.6 months 95% CI [18.4, 77.9]. Conclusions: Although limited by the sample size, our data suggests that HER-2 low breast cancer tends to be more locally advanced or metastatic at the time of presentation. HER-2 low BC is associated with a higher Ki-67 index and tends to harbor more mutations. HER-2 low may not just be a target, but a unique biological entity and can be distinguished from HER2-Zero BC with higher prevalence of HR+ and other biomarkers and better OS. NGS data from a larger data set is required to better characterize HER-2 low breast cancer. We suggest that clinicians obtain NGS panel in all patients with HER-2 low MBC. [Table: see text]
The role of stress in modulating AIPB expression and estradiol synthesis in triple-negative breast tumors.
Authors: Mahjabin Patrawala, Himangshu Bose
Journal: Journal of Clinical Oncology (2024)

e13146 Background: In the United States, invasive breast cancer affects 1 in 8 women during their lifetime, with over 3.8 million individuals living as survivors. Breast cancers vary, with some being hormone-responsive and categorized on the presence or absence of estrogen (ER), progesterone (PR), and HER2 receptors. While targeted therapies exist for Estrogen Receptor positive (Er+) and Progesterone Receptor positive (PR+) cancers, triple-negative breast cancer (TNBC), which lacks all three receptors, affects about 15% of patients and is unresponsive to effective molecular treatments. Only a fraction of the cases respond to chemotherapy which emphasizes a need for new prognostic markers and treatments. Aromatase is the key enzyme in converting testosterone to estradiol which plays a crucial role in tumor growth, especially after menopause. Our research lab has identified the “Aromatase Interacting Partner in Breast or AIPB, whose overexpression inhibits aromatase, leading to a reduction in estradiol levels. However, in triple-negative breast cancer, there is an increase in AIPB expression when compared to ER+/PR+/Her2- breast tumors or unaffected women. This devastating prognosis and low survival rates can contribute to a considerable amount of stress in the diagnosed patients, in turn leading to an increase in cortisol production. Our hypothesis suggests that this stress or increase in cortisol could alter AIPB production in the tumorigenic cells which could potentially lead to a decrease in estradiol synthesis. Methods: Stress stimulation was achieved in a lab setting by subjecting engineered triple-negative breast cancer cells, capable of conditional AIPB overexpression upon tetracycline addition, to a 42 °C heat shock for various durations (0,15, 30, 45 minutes). Results: Following the 45 minutes of stress, MDA-MMD-231 cells exhibited a significant reduction in estradiol levels, decreasing from 160ng/ml to 100ng/ml. MDA-MD-231 cells engineered to overexpress AIPB produced only 62ng/ml of estradiol, marking an 18.75% decrease. The introduction of doxycycline led to a further reduction in estradiol levels to 47ng/ml, which is approximately a 29.4% drop. Western blot analysis using a CT antibody revealed heightened AIPB expression in MDA-MD-231-AIPB cells when stress and doxycycline treatments were combined. Conclusions: Given the absence of aromatase in triple-negative breast cancer, our findings suggest that AIPB’s role in estradiol production is independent of aromatase, highlighting its significance in these cancer cells. The data supports the hypothesis that enhancing AIPB expression could potentially improve patient outcomes by reducing estradiol synthesis.
Mutations and mortality in very young patients with breast cancer.
Authors: Raina Saxena, Victoria Chung, James Peeples, Yanming Yang, William Song, Susan Olet, Melanie Anne Sheen
Journal: Journal of Clinical Oncology (2024)

e13157 Background: Breast cancer diagnoses in young women have increased over the last 10 years. Despite decreasing mortality rates for breast cancer, disparities continue to exist for specific populations including Black women and premenopausal women. Recent studies observe a 41% increased death rate in Black women compared to White women, and a two-fold increased mortality in women younger than 50 years. Many biological and societal factors can affect breast cancer mortality. We sought to evaluate the relationship between germline mutations (GM), breast cancer subtype, and mortality based on race in a unique, young breast cancer patient population. Methods: We assembled a 10-year retrospective chart review (2012 to 2022) of 773 women diagnosed with breast cancer under the age of 40 in a regional health network. Data was collected from electronic medical records. Associations were assessed using the chi-square test using SAS version 9.4. Results: Out of the 773 patient information collected, 60% of patients were White, 36% Black, and 3% Other. A total of 675 patients had genetic results and 124 patients with documented GM. Of patients with GM, 48 were Black and 74 were White. 13 patients with germline mutations had documented deaths. There was no statistical link between germline mutations and mortality. Of the 13 patients, 4 (30%) were Black and 9 (70%) were White. There was no statistical difference amongst area deprivation index (ADI) quintiles for mortality in patients with GM. Of the 675 patients with genetics data, 72 patients without GM died which includes 31 Black patients, 38 White patients, 3 Other. Based on our data, there is a higher prevalence of germline mutations (60%) in White patients over Black patients and a descriptive predominance of mortality despite absence of statistical significance. More patients who resided in areas of higher ADI (2-4) with GM died than in areas of lower ADI. Conclusions: Our data demonstrates a descriptive prevalence in mortality among young White patients compared to young Black patients. Across the USA, the Black population is 13% and in Louisiana, that population is 33%. Given that our cohort population was 36% Black, it is noteworthy that we were unable to demonstrate a statistical mortality predominance among these young patients. [Table: see text]
Frequency of HER2-Low in breast cancer biopsies in Chile.
Authors: Martín Vidal, Alvaro Rivera, Constanza Schuler, Nicolas Garnham, Elisa Alcalde, Pablo Pinto Ahumada, Alex Renner
Journal: Journal of Clinical Oncology (2024)

e13163 Background: In breast cancer (BC), human epidermal growth factor receptor 2 (HER2) is a prognostic and predictive biomarker. Traditionally, the use of HER2-targeted therapies is reserved for BC that overexpress HER2, defined as immunohistochemical (IHC) expression of 3+ or 2+ with amplification of the gene encoding HER2, detected by in situ hybridization (ISH). Recently, the term HER2-Low, defined as the IHC expression of 1+ or 2+ with negative ISH, has gained relevance as a new predictive biomarker for the use of trastuzumab-deruxtecan. The frequency of HER2-Low BC in the Chilean population is unknown. The objective of this study is to show the frequency of HER2-Low BC in a Chilean center. Methods: Descriptive cross-sectional analysis of clinical records and biopsies of localized or metastatic invasive breast carcinoma performed at Clínica Santa María between January 2020 and December 2023. The IHC expression of the estrogen receptor (ER), progesterone receptor (PR), Ki-67, HER2, histological grade (G) and HER2 in situ hybridization (ISH) when appropriate. The frequency and characteristics of HER2-Low cases are described and compared with the surrogate clinicopathological subtypes luminal A, luminal B (HER2-Positive and Negative), HER2-Positive and Triple Negative (TN), according to the St Gallen Consensus Conference 2013. Results: Between January 2020 and December 2023, a total of 339 biopsies with invasive BC were identified, from which 104 (36.0%) met the definition of HER2-Low. The frequency of luminal B and luminal A that met the definition of HER2-Low was 54 (51.9%) and 40 (38.5%), respectively. Of the 253 biopsies classified as luminal, 94 (37.2%) met the definition of HER2-Low, while of the 36 biopsies classified as TN, 10 (27.8%) did. Luminal B HER2-Negative and TN surrogate subtypes that met the definition of HER2-Low had a higher frequency of G3 than their non-HER2-Low counterpart. Conclusions: In the population analyzed, a considerable percentage of cases meet the definition of HER2-Low. This has relevant therapeutic implications. Distribution of biopsies that meet HER2-Low criteria according to surrogate clinicopathological subtype of breast cancer. [Table: see text]