bluuebunny/crossref_metadata_2025 huggingface dataset:
Evaluating the efficacy of neoadjuvant endocrine therapy in HER2 low vs. HER2 negative breast cancer: An NCBD analysis.
Authors: Chong Esther G , Guo Mengni , Castillo Dani Ran , Bazan Jose G. , Yap Kelly Khai Li , Schultz-Costello Katharine , Wu S.Peter
Published: June 2024

599

Background: Neoadjuvant endocrine therapy (NET) is an important treatment option for hormone receptor (HR)-positive breast cancer (BC). Innovative ADCs targeting HER2 low tumors has sparked debate regarding the distinct nature of HER2 low tumors and whether it merits a unique treatment approach. With favorable outcomes in metastatic disease, there is interest in adopting similar strategies for early-stage treatment approaches. Methods: We examined the National Cancer Database for stage I-III ER-positive BC in women who underwent neoadjuvant endocrine therapy (NET) from 2010 to 2017, for at least 90 days to a maximum of 270 days. Patients with prior neoadjuvant chemotherapy, other malignancies, HER2-positive disease by either IHC or FISH, metastatic disease, or unknown stage were excluded. HER2 status was grouped as negative or low per 2023 ASCO-CAP guidelines. Patients’ response to therapy included pathologic complete response (CR), partial pathologic response (PR), stable pathologic response, or progression in primary tumor at time of resection. We employed multivariable binomial logistic regression to examine how clinicopathologic factors influence the probability of any response (combining CR and PR) to neoadjuvant hormonal therapy. Results: 3,808 patients met the inclusion criteria. 1,055 (27.8%) patients had HER2 negative disease, and 2,753 (72.2%) patients were HER2-low. 48 (1.2%) patients had primary tumor CR, and 1,484 (39%) had PR. Among HER2-low patients, 37 (1.3%) had pathologic CR, and 1,134 (41.1%) had PR. Among HER2-negative patients, 11 (1.0%) had pathologic CR, and 350 (33.1%) had PR. Multivariable logistic models revealed that age, duration of NET, and HER2 status were significant predictors of any response to NET. HER2-low tumors were more likely to have any response compared to HER2-negative (aOR=1.16, 95% CI 1.01 - 1.34, p=0.04). Patients who received >150 days of hormonal therapy were more likely to respond (aOR=1.33, 95% CI 1.16 - 1.52, p=<0.001); patients >50 years old were more likely to have any response (aOR=1.41, 95% CI 1.07 - 1.90, p=0.02). Clinical node positivity and tumor grade did not have significant effect on response to NET at time of resection. Conclusions: Our study offers a real-world estimate of outcomes associated with NET in localized BC. HER2 low tumors had greater significant clinical responses to NET when compared to HER2 negative, suggesting that HER2 low tumors may benefit from tailored treatment in the neoadjuvant setting. [Table: see text]
HER2 low hormone positive breast cancer: Unveiling the driver.
Authors: Eltelbany Alaa , Elsheredy Heba , Elsaka Rasha , Elnowiem Saied A. , Arafat Waleed O.
Published: June 2024

e12561

Background: A new HER2 targeting drug, Trastuzumab deruxtecan, has shown effectiveness among a subgroup of breast cancer (BC) patients previously reported as HER2 negative, challenging the established classification. HER2 low (IHC 1+ or IHC +2/ISH negative) require further study to understand their clinicopathological features and prognosis to determine whether they are indeed distinctly different from the HER2 negative subgroup. Methods: This retrospective study of 1029 early BC patients diagnosed between 2014 and 2022 in Alexandria university hospitals. Tumors originally reported as HER2 negative were reclassified into HER2 0 and HER2 low and stratified based on hormone receptor (HR) status. Clinical and pathological features were compared. Disease free survival (DFS), overall survival (OS) and time to recurrence (TTR) were calculated. Results: Out of the 1029 patients, 779 (75.7%) were reported as HER2 negative, after reviewing their files, 441 (56%) of them were found to be IHC 0, and 338 (43%) were HER2 low. 192 (18.7%) HER2 positive patients and 58 (5.6%) patients with undetermined HER2 status were excluded. HER2-low tumors were found to be positively associated with HR positive status compared to HER2-0 (302 [89.3%] vs. 368 [83.4%]; P=0.019). The rate of HER2-low significantly increased as the level of ER expression increased, from 37 of 190 (19.5%) ER-negative to 40 of 143 (28%) ER-low, 94 of 264(35.6%) ER-moderate and 167 of 432(38.7%) ER strong, p=<0.001. ER2-low were more likely to be ductal carcinoma (88.1% vs. 80.4%; p=0.004), and to have Ki67 level <20 (55% vs. 33%; p=0.008). When stratified according to HR status, ductal histology was still significantly higher in the HER2 low HR positive subgroup compared to the HER2-0 HR positive (87.6% vs. 80.3%; p=0.011). No significant difference between HER2-0 and HER2-low regarding age at presentation, menopausal status, tumor size, lymph node status, lymphovascular invasion, high grade, multifocality or extensive intraductal component. Median follow-up duration was 55 months, no significant differences between HER2-0 and HER2 low groups regarding relapse rate (22.6% vs. 21.6%), 5-year DFS (76.4% vs. 78%) or 5-year OS (81.7% vs. 87.4%), however TTR was significantly longer in the HER2 low HR positive group compared to the HER2-0 HR positive group (41.6 months vs. 31.3 months; p= 0.031). Conclusions: A positive correlation was observed between HER2 low and estrogen receptor positivity, as well as its level of expression. No significant differences were found between HER2 low and HER2-0 to support classifying HER2 low as a distinct group.
A set of molecular biomarkers as an indicator of cancer risk.
Authors: Singhal Sonalika , Gardner Kevin , Singhal Sandeep K. , Sens Donald
Published: June 2024

e12563

Background: Biomarkers are molecular indicators of a biological status and are often used to determine the presence or absence of cancer Molecular changes in both in of cancer cells and their surrounding environment including, blood other body fluids, and tissues that react to the cancer provide biomarker materials that may be effective predictor of disease risk or disease outcome. Effective biomarkers for the disease associated risk and early detection of cancer improves potential patient outcome. An emerging theme is to develop multi-omics panels of biomarker with sufficient sensitivity and specificity for the pre-symptomatic detection of cancer. We applied approximately 300 genomics and proteomics-based genomics (PbG) biomarkers, to identify a panel of biomarkers associated with different types of cancers using patient and donor RNA samples collected from platelets Platelet RNA mirrors the RNA of nucleated cells and can be an important indicator of tissue states particularly in under pro-inflammatory conditions [PMC9555784]. Methods: Publicly available RNA-seq data of N = 2351 blood platelet samples, (including n= 390 asymptomatic controls) from 18 different tumor types was analyzed to identify the panel of biomarkers associated with highest risk cancers. Approximately 300 genomic and PbG signatures (developed from gene expression-based signatures on patients stratified according to protein expression (IHC) and survival. The predictive value of each gene signature (including commercial once ROR, OncotypeDx, etc.) was evaluated by logistic regression modeling in univariate and multivariate settings. Results: Out of 300 biomarkers, we found a set of PbG biomarkers including ratio of BRG1 expression between nuclear and cytoplasm, cytoplasmic C-terminal-binding protein 2 (CtBP2) in express in cytoplasm and ratio of nucleus and cytoplasm, Nucleus Tripartite motif-containing 28 (TRIM28), Vascular endothelial growth factor (VEGF), Mitogen-activated protein kinases (MAPK), androgen receptor (AR) express in Nuclear vs cytoplasm, Glycoprotein 78 (Gp78) in cytoplasm, E2F3, and a member of the epidermal growth factor (EGF) receptor family (ERBB2) are highly predictive (0.77 (0.76 ~ 0.79)) of cancer associated risk on a multivariate training/validation setting. The BRG1 biomarker has the highest odds ratio (11.33) within model, known for coordinating and maintaining key signaling pathways that promote oncogenesis in different cancer types including leukemia, breast, and prostate cancer. Cancer Risk model = 3.4 - 1.01 ERBB2 + 0.3 GP78_Cyto - 3.2 AR_Nucl + 0.7 CtBP2_NucVsCyto - 0.3 E2F3 - 0.99 AR_NucVsCyto + 0.87 VEGF - 1.9 MAPK + 2.43 BRG1_NucVsCyto + 1.35 TRIM28_Nucl + 1.23 CtBP2_Cyto. Conclusions: Utilizing novel genomic, and proteomic technologies, risk prediction and early detection of cancer could identify patients at a time when outcomes are superior and treatment is manageable. Further evaluation of this model is recommended.
Coping with inter-observer variability when assessing AI for scoring of HER2-stained whole slides.
Authors: Thomas Florian , Pommeret Denys , Guinaudeau Emmanuelle , Poulet Bruno , Salhi Yahia , Chetritt Jérôme
Published: June 2024

e12571

Background: Around 15% of breast carcinomas exhibit Human Epidermal growth factor receptor 2 (HER2) overexpression due to gene amplification. HER2 protein levels are assessed by Immunohistochemistry (IHC) with 4 scores (0, 1+, 2+, 3+). Only score 3+ (IHC) cases and score 2+ (IHC) with proven HER2 gene amplification are eligible for targeted anti-HER2 therapies; others are HER2-negative. However, tumors with score 1+ and 2+ not amplified could benefit from treatment with the new HER2-based antibody-drug conjugates, requiring an accurate HER2 scoring, which is challenged by interobserver variability. This drawback is challenging for AI-based HER2 scoring assessment, and it is thus important to understand this inter-variability and then be able to propose a probabilistic framework which quantifies and explains the discrepancy between the AI analysis and the pathologist scoring. Methods: We introduce a novel probabilistic framework designed to assign probabilities to scores generated by AI algorithms. To the best of our knowledge, this represents the pioneering effort to quantify the uncertainty surrounding AI predictive models for HER2 scores. The methodology relies on a high-dimensional multivariate Gaussian approximation of the HER2 scoring process, hinting on the precise identification of marked cells to a specified category based on membrane completeness and staining intensity. Introducing uncertainty in the categorical identification enables the quantification of uncertainty in the overall AI-scoring at the whole slide image (WSI) level. Consequently, instead of offering a singular score, we can allocate a probability of belonging to a particular category (0, 1+, 2+, or 3+) for the global score. This approach enables a comparison of the predicted likelihood with the distribution of scores among pathologists, rather than relying on a "hypothetical" ground truth, often determined by a majority-voting which can be noise-sensitive or which excludes ambiguous cases when an agreement is hard to reach. Results: For illustration, we use the Kwant HER2 algorithm developed by DiaDeep on a validation set of 68 HER2 cases, previously scored by three expert pathologists. The framework allows us to understand the discrepancy between pathologists as we introduce nuance to the AI scoring and underlines narrow probability margins in borderline cases, therefore depicting the inherent challenge for pathologists to draw a clear demarcation between closely aligned scores categories. Conclusions: The proposed framework underscores the intrinsic variability of HER2 scoring between pathologists and allows to analyze the AI predictions for HER2 scoring with more nuance, consequently enabling a more critical analysis of the results compared to a singular raw output. As we enter a new era of AI-assisted diagnosis, such a method could improve the way of assessing new AI tools and help interpret their results.
SE-GAP-ResNet: A machine learning model for abnormal breast detection.
Authors: Gorriz Saez Juan Manuel , Wang Shuihua , Zhang Yudong
Published: June 2024

e12579

Background: Breast cancer is the most common cancer in women worldwide. Although screening has improved early-stage detection, challenges like high false positives and heavy workloads for radiologists persist, emphasizing the importance of early identification of breast irregularities, including masses and micro-calcifications. Methods: We use a subset of the mini-MIAS dataset, randomly choosing 100 abnormal and 100 healthy images, with abnormal images categorized into six sub-types. Preprocessing involves removing noises and excluding background and muscle regions. Our classifier is the ResNet-34 model, a deep convolutional neural network with 34 layers, known for effective pattern identification in medical images. Enhancements include: (1) The Squeeze-and-Excitation (SE) block boosts neural network discriminative power by dynamically recalibrating channel or feature importance. Integrated into ResNet-34, it forms the backbone network, enhancing the identification of relevant patterns for improved diagnostic accuracy. (2) Complex patterns at the system's output are condensed into a common disease pattern through global average pooling (GAP). This reduces model parameters, enhances interpretability, and facilitates the extraction of essential diagnostic information from the entire image. (3) Feature vectors from different layers are concatenated to merge low-level and high-level features. Low-level features encompass fundamental visual attributes such as pixel intensity and texture, while high-level features involve more complex patterns and structures, including organ shapes and anomalies. (4) We employ multiple-way data augmentation techniques to augment the training set, including rotation, translation, scaling, Gamma correction, and shear. The resultant model is referred to as SE-GAP-ResNet. Results: After 10 iterations of 10-fold cross-validation, SE-GAP-ResNet exhibited notable performance with a sensitivity of 95.60%, specificity of 93.30%, precision of 93.49%, accuracy of 94.45%, and an F1 score of 94.51%. Outperforming three state-of-the-art approaches, as shown in the table, two-sample t-tests confirm that SE-GAP-ResNet achieves significantly superior performance (p<0.05). Conclusions: SE-GAP-ResNet excels in identifying breast abnormalities. We aim to enhance the AI system by adding a multi-class diagnosis framework and the capability to predict lesion regions, with the goal of substantially reducing callback rates for abnormal breast diagnoses and improving diagnostic accuracy and efficiency. [Table: see text]
Predicting peripheral neuropathy following neoadjuvant therapy in patients with breast cancer.
Authors: Feiger Bradley , Biancalana Matthew , Shelton Amy , Blenman Kim , Lustberg Maryam B.
Published: June 2024

e12639

Background: Administration of neoadjuvant chemotherapy (NACT) or radiation is widely used to improve outcomes in patients with breast cancer. This strategy has demonstrated remarkable efficacy in reducing tumor burden and increasing the likelihood of breast-conserving surgery. However, neoadjuvant therapy can induce peripheral neuropathy, a condition characterized by nerve damage or dysfunction in the extremities that often manifests as pain, tingling, or weakness in the hands and feet. The exact mechanism remains unclear, although likely involves the cumulative toxic effects of therapy on peripheral nerves. Treatment-induced neuropathy poses a substantial unaddressed challenge that can significantly impact the patient’s quality of life. Therefore, predicting and ameliorating neuropathy are crucial aspects of comprehensive cancer care. Methods: We used an AI spatial biology platform to create and assess 3D depictions of a cohort of breast cancer patients based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data. Clinical, pathological, and radiological data were collected on 74 patients from Yale New Haven Hospital. Due to missing regimen data, the final dataset included 71 patients, with mean age 51.1 (14.5) years. An AI-based segmentation algorithm was successfully employed on 63 patients, of whom 13 had neuropathy following NACT. Vascular and microvascular (MV/V) kinetic parameters were computed for each, and radiomic features were extracted. Machine learning models were developed for clinical features, MV/V features, and the combined set of features. All models were tested with leave-one-out cross-validation. Results: The clinical model did not forecast neuropathy in any patient, indicating poor predictive ability. The MV/V model performed the best, with accuracy, precision, recall, and AUROC of 0.84, 1.0, 0.18, and 0.69, respectively. The combined model showed intermediate performance, with accuracy, precision, recall, and AUROC of 0.81, 0.5, 0.18, and 0.58, respectively. The patient population limits broad conclusions, but suggests features that are aligned with increased occurrence of neuropathy. In particular, vascular features that describe transfer of nutrients between tissues, as well as the density of blood vessels within and around the tumor, are prominent within both the MV/V and combined models. Conclusions: These results indicate that features associated with the degree of proximal and intratumoral vascularity may be predictive of peripheral neuropathy in breast cancer patients. Moreover, these features can be extracted from standard-of-care DCE-MRI data. Expansion of this vascular analysis could enable physicians to better plan and manage care for patients by tailoring treatment dose. [Table: see text]
The effects of anlotinib combined with chemotherapy following progression on cyclin-dependent kinase 4/6 inhibitor in hormone receptor-positive metastatic breast cancer.
Authors: Xu Ting , Zhang Lili , Yuan Yuan , Hu Sainan , Dong Min , Xu Xinyu , Huang Jiayuan , Xiong Weili , Lou Kexin
Published: June 2024

e13052

Background: Endocrine therapy combined with cyclin-dependent kinase (CDK) 4/6 inhibitors (CDK4/6i) is the preferred treatment for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (MBC). However, there are currently no recommendations for therapeutic strategies after progression on CDK4/6i-based treatment. This study aimed to examine the efficacy and safety of anlotinib plus chemotherapy in HR+/HER2-MBC after progression on CDK4/6 inhibitors. Methods: We collected data from 32 patients with HR+/HER2– MBC treated with anlotinib plus chemotherapy after progressing on CDK4/6i at Jiangsu Cancer Hospital from March 2020 to October 2023. The median follow-up was 9.1 months (range, 2.0-19.7 months) as of the data cutoff date in October 2023. The primary endpoint was median progression-free survival (PFS), secondary endpoints included objective response rate (ORR), disease control rate (DCR), and adverse events. Results: The median PFS (mPFS) of all patients was 7.6 months [95% confidence interval (CI), 5.75-9.45]. There was no significant difference in mPFS between patients who responded to prior CDK4/6i treatment and those who did not. (8.3 months versus 6.8 months, p = 0.580). Besides, the ORR was 34.4% and DCR was 93.8%. The most frequently observed adverse events were anemia (50.0%), neutropenia (40.6%), thrombocytopenia (34.4%), and epistaxis (34.4%). Dose interruption or reductions due to adverse events occurred in 2(6.3%) and 5 (15.6%) patients, respectively. Conclusions: The study preliminarily demonstrates that anlotinib combined with chemotherapy may be an optional recommendation for patients with HR+/HER2- metastatic breast cancer who have progressed after CDK4/6i.
Effect of timing of recurrence on outcomes in patients with metastatic breast cancer treated with CDK4/6 inhibitors.
Authors: Niraula Sujan , Villamarin Diego , Smith Tae , Babbra Ramandeep , Mahant Akhil , Strawderman Myla S. , Kharel Zeni , Tinkham Christie , Tiongson Michael , Bamarajpet Nikhil , Houshyar Samin , Kim Erica , Weiss Anna , Falkson Carla Isadora , O'Regan Ruth , Zhang Huina , Dhakal Ajay
Published: June 2024

e13067

Background: CDK4/6 inhibitors (CDKi) + endocrine therapy (ET) comprise the standard 1st line treatment for ER+ HER2- metastatic breast cancer (MBC). However, there is a gap in understanding how timing of MBC recurrence affects clinical outcomes on CDKi. We conducted a study to compare clinical outcomes of MBC patients on CDKi based on timing of MBC recurrence. Methods: This retrospective study enrolled ER+ HER2- MBC patients diagnosed from Jan 2015 to Jan 2023, who received CDKi + ET as 1st line treatment for MBC. Patients were categorized as de novo MBC (dMBC), if they had 1. Stage 4 disease at initial diagnosis or 2. MBC diagnosed < 6 months of the primary breast cancer (PBC) diagnosis and before starting any systemic treatment for PBC. Patients with distant recurrence occurring < 5 years, 5-10 years, and >10 years from PBC were categorized as early, intermediate, and late MBCs (eMBC, iMBC, laMBC). Endpoints were Progression-Free Survival (PFS) and Overall Survival (OS) from MBC diagnosis. Baseline variables were compared using t-tests (continuous) and Chi-square tests (categorical). Endpoint analyses were conducted using Kaplan-Meier method and compared using Log rank test. Multivariate analyses were performed using Cox models. Results: Out of 280 patients enrolled, 67 were dMBC, 75 eMBC, 56 iMBC, and 82 laMBC. The laMBC group had a higher mean age (years) compared to other groups (71 vs. 62 in dMBC+ eMBC + iMBC, p<0.001). 64.5% of laMBC had visceral disease compared to 50.5% of dMBC + eMBC + iMBC (p=0.031). 65.7% of dMBC patients were treated with palbociclib compared to 80.8% of eMBC + iMBC + laMBC (p=0.010). Higher % of eMBC were PR- vs other cohorts (41.3 vs 23.9 dMBC + iMBC + laMBC, p<0.001). Among the 3 non dMBC groups, prior ET sensitivity (no recurrence for 2 years on adjuvant ET) was lower in eMBC (45.3%) compared to iMBC + laMBC (81.9%, p<0.001). 61.3% of eMBC patients were on adjuvant ET at recurrence compared to 17.4% of iMBC + laMBC (p<0.001). Other variables were similar. Table shows unadjusted endpoint analyses. In multivariate analyses, the risk of PFS events were not significantly different among cohorts (age<=65, ECOG performance status (PS) >=2 and PR- were independently associated with shorter PFS); risk of death was higher in eMBC vs laMBC (HR 1.73, p=0.047). Conclusions: In this retrospective study of ER+ HER2- MBC patients treated with 1st line CDKi + ET, timing of MBC recurrence was not associated with PFS differences after adjusting for other variables. However, patients with MBC recurring < 5 years of PBC had the higher likelihood of death compared to those recurring >10 years of PBC. [Table: see text]
The association of hormone receptor expression level and clinical efficacy of CDK4/6 inhibitor in hormone receptor-positive, HER2-negative metastatic breast cancer.
Authors: Bao Kelvin K. H. , Wong Carol HY , Yung Jackie , Tam Venus , Cheung Ka Man , Chan Jeffrey CH , Yiu Harry HY
Published: June 2024

e13069

Background: In patients with hormone receptor-positive, HER2-negative metastatic breast cancer (HR+ HER2- MBC), the correlation between the level of expression of HR and the clinical efficacy of CDK4/6 inhibitors remains undefined. Methods: We identified consecutive patients with HR+ HER2- MBC starting a CDK4/6 inhibitor (palbociclib, ribociclib or abemaciclib) plus either an aromatase inhibitor or fulvestrant between Jan 2018 - Oct 2023 from an institutional cancer registry. Expression level of HR was stratified as high (H) (Allred score 7-8), moderate (M) (Allred score 5-6) or low (L) (Allred score 3-4) for both estrogen (ER) and progesterone receptors (PR). Patients were evaluated from start of treatment to December 2023, last visit or death, whichever came earlier. Median progression-free survival (mPFS) and overall survival (mOS) were endpoints. We evaluated the association of HR expression levels with mPFS and mOS using log-rank test and multivariate Cox regression modelling. Results: We examined data from 436 women with HR+ HER2- MBC. Median age at treatment was 60.5 yr. Majority of patients received the treatment in the first-line setting (72.5%), with palbociclib (54.1%), ribociclib (31.9%) and abemaciclib (14.0%) as the CDK4/6 inhibitor. In the population that received first-line treatment, ER expression levels were H (83.5%), M (11.4%) and L (5.1%) respectively. ER expression levels were strongly associated with mPFS and mOS. For ER H, M and L expressions, mPFS were 29.4m, 9.2m and 2.9m ( p<0.001); mOS were 52.1m, 40.6m and 11.6m ( p<0.001), respectively. In multivariate analysis, ER expression levels remain strongly predictive for both mPFS and mOS after adjustment for clinicopathological risk factors (ER L vs H, mPFS HR 10.6, p<0.001; mOS HR 4.66, p<0.001; ER M vs H, mPFS HR 4.90, p<0.001; mOS HR 2.06, p=0.05). Findings were similar for the second line and beyond population. In the ER-high expression cohort, the PR expression levels also correlate strongly with treatment efficacy and survival, with mPFS of 40.8m, 24.5m, 24.0m, 14.1m ( p<0.001) and mOS of NR, 53.3m, 48.1m, 26.9m ( p<0.001) respectively for PR H, M, L and zero expressions. Conclusions: In this real-world cohort of patients with HR+ HER2- MBC, we observed that the semi-quantitative HR expression level subgrouping is a strong predictor for the efficacy of treatment with CDK4/6 inhibitors. In contrast to patients with high HR expression levels, the small population with ER-low expression derived very limited benefits from the standard endocrine therapy with CDK4/6 inhibitors. Our findings provided a practical tool to guide the selection of the appropriate systemic therapy for individual patients.
How overall survival is conditioned in the progression to treatment with cyclin inhibitors plus endocrine treatment in metastatic breast cancer with luminal phenotype.
Authors: Prieto Garcia ANA , Morales Murillo Serafin , Tuset Der-abrain Noemí , Rodriguez Gonzalez Gara , Gasol Cudos Ariadna
Published: June 2024

e13079

Background: CDK4/6 inhibitors plus endocrinotherapy (ET) is the standard first-line treatment for metastatic breast cancer with a luminal phenotype. However, the response to this treatment is highly dependent on its previous efficacy. Methods: We analyzed the overall survival in a cohort of 127 patients with metastatic luminal breast cancer in progression after treatment with CDK4/6 inhibitors plus ET. Results: The median age of the group was 67 years (41-96), the interval time between initial diagnosis and first recurrence was 0 in 41 (32%), 1-60 months in 37 (29%) and more than 60 months in 39 (38%). The first line in the metastatic setting was CDK4/6 plus ET in 81 patients (64%), ET in 15 (12%) and 31 (24%) were treated with chemotherapy. The status of HER2 expression was HER2 low in 77% and 43 % had visceral metastases disease. The median progression-free survival for the patients treated with CDK4/6 inhibitors plus ET was 9 months, with a total of deaths of 69 (55%). Overall survival after progression on CDK4/6 plus ET was 38 months (28 – 47) and the most important factor for overall survival was the response time to treatment with CDK4/6 inhibitors plus ET. Conclusions: The most important factor for overall survival is the duration of treatment with CDK4/6 inhibitors plus ET. Patients with a response time of less than 6 months had a median overall survival after progression of 11 months (3 – 19), while the 6- to 12-month group had a median of 39 months (19 – 59) and the group with more than 12 months had the best prognosis with a median overall survival of 53 months (37 – 68). We need to improve the new treatment options for patients who respond for less than 6 months to treatment with CDK4/6 plus ET.
Toxicity differences in CDK 4/6 inhibitors seen in Asian and Pacific Islanders.
Authors: Gushiken Brooke , Braun-Inglis Christa M. , Workman Tyler , Fukui Jami Aya
Published: June 2024

e13086

Background: Cyclin-dependent kinases (CDK) 4/6 inhibitors are the standard of care, first line treatment for hormone receptor positive metastatic breast cancer and adjuvant high-risk hormone receptor positive early stage breast cancer along with endocrine therapy. There have been multiple clinical trials validating the effectiveness, along with toxicities of these agents; however, the majority of these trials lack ethnic diversity. This shortcoming limits the ability to apply these findings in diverse patient populations, especially among Asian and Pacific Islanders in Hawaii. Objective: To determine if the toxicity profile of CDK 4/6 inhibitors in women with breast cancer is different among patients at a community oncology practice in Hawaii, in which the majority of patients are Asian, Pacific Islander or a combination of both when compared to three landmark trials. Methods: A retrospective analysis of thirty-two patients with hormone receptor positive, HER2 negative metastatic or high risk breast cancer who started endocrine therapy and CDK 4/6 inhibitor therapy (abemaciclib, ribociclib, or palbociclib) between 2018-2023. Graded toxicities of each individual patient based on CTCAE criteria V. 5, along with demographic data was reviewed and compared to three main registration trials for these agents (MONARCH-3, MONALEESA-2, PALOMA-2). Results: Combined results from the three large randomized trials reported an average of 75% of participants were Caucasian, as compared to 15% in the Hawaii data. While 19% percent of participants from the combined large randomized trials reported being of Asian descent, none of these trials reported a breakdown of Asians versus Pacific Islanders. In the Hawaii sample, 41% were reported as Pacific Islander and 41% reported as Asian, 15% Caucasian, with the final 3% reported as Hispanic. Collective analysis of the FDA registration trials contained 0% Pacific Islander, 19.8% Asian, 74.3% White, 1.5% Black, and 4.4% Other. The majority of all toxicities of all grades were higher in the Hawaii population as compared to the three national trials, except for neutropenia with ribociclib and diarrhea with palbociclib (Table). Conclusions: The Hawaii analysis that was primarily comprised of Asians and Pacific Islanders revealed an increased incidence of toxicities, despite starting at lower doses rates for all CDK 4/6 inhibitors. This data analysis begins to highlight the importance of representative populations in clinical trials for the most effective and safest care of diverse populations. [Table: see text]
Body composition measures as a determinant of alpelisib-related toxicity.
Authors: Shachar Eliya , Raphael Ari , Katz Uriel , Kessner Rivka , Strulov Shachar Shlomit
Published: June 2024

e13093

Background: Body composition has emerged as an important prognostic factor in patients treated with cancer. Severe depletion of skeletal muscle, sarcopenia, has been associated with poor performance status and worse oncological outcomes. We studied patients with metastatic breast cancer receiving alpelisib, to determine if sarcopenia and additional body composition measures accounting for muscle and adiposity are associated with toxicity. Methods: A retrospective observational analysis was conducted, including 38 women with metastatic breast cancer and a PIK3CA mutation, treated with alpelisib as advanced line of therapy. Sarcopenia was determined by measuring skeletal muscle cross-sectional area at the third lumbar vertebra using computerized tomography. Various body composition metrics were assessed along with drug toxicity, dose reductions, treatment discontinuation, and hospitalizations. Results: Sarcopenia was observed in half of the patients (n=19, 50%), spanning normal weight, overweight, and obese individuals. Among the body composition measures, lower skeletal muscle density (SMD) was associated with an increased risk of treatment-related hyperglycaemia (P=0.03). Additionally, lower visceral adipose tissue (VAT) was associated with alpelisib-induced rash (P=0.04) and hospitalizations (P=0.04). Notably, alpelisib treatment discontinuation was not impacted by alpelisib toxicity. Conclusions: Body composition measures, specifically SMD and VAT may provide an opportunity to identify patients at higher risk for severe alpelisib related hyperglycemia, and cutaneous toxicity. These findings suggest the potential use of body composition assessment to predict toxicity, allowing for personalized therapeutic observation and intervention.
Co-occurrence of ESR1 and PIK3CA mutations in HR+/HER2- metastatic breast cancer: Incidence and outcomes with targeted therapy.
Authors: Dempsey Naomi , Bhatt Priya , Lewis Courtney , Tolman Dana , Chamorro Yolcar , Rubens Muni , Carcas Lauren , Sandoval-Leon Ana Cristina , Ahluwalia Manmeet Singh , Mahtani Reshma L. , Harpalani Natasha
Published: June 2024

e13097

Background: ESR1 and PIK3CA mutations inform the use of targeted agents such as alpelisib (A), elacestrant (E), and capivasertib in patients (pts) with HR+/HER2- metastatic breast cancer (mBC). These mutations predict a worse prognosis and shorter response to endocrine therapy (ET). The prevalence of PIK3CA and ESR1 mutations detected via circulating tumor DNA (ctDNA) in mBC is about 35% and 33%, respectively, and the co-occurrence rate is 10-15%. Treatment outcomes with these targeted agents in pts with both mutations can inform sequencing decisions. Methods: We retrospectively analyzed pts treated at Miami Cancer Institute with HR+/HER2- mBC who underwent ctDNA testing (performed by Guardant360) between March 2019 and Jan 2024. The rate of co-occurring pathogenic ESR1 and PIK3CA mutations on a single sample was quantified. We report pt demographics, disease characteristics, and real world outcomes on A + ET and E in the co-mutated cohort. Results: Of the 626 pts who underwent ctDNA testing, 31.6% (n=198) had at least one PIK3CA mutation and 23.8% (n=149) had at least one ESR1 mutation. Co-mutations in both ESR1 and PIK3CA were found in 10.4% (n=65). In the co-mutated cohort, median age was 63, 84.6% were post-menopausal, and 58.5% were Hispanic. Most pts received prior CDK4/6 inhibitor (90.7%). A + ET was administered to 27 pts (41.5%) with a median of 2 prior lines of therapy (range 1-8). In these pts, 33.3% (n=9) achieved stable disease, 25.9% (n=7) partial response, 14.8% (n=4) progression, and 18.5% (n=5) discontinued due to toxicity prior to re-staging. E was administered to 12 pts (18.5%) with a median of 4 prior lines of therapy (range 1-13), with 4 pts still on treatment. None achieved stable disease or objective response, 66.7% (n=8) developed progression of disease as best response, and 33.3% (n=4) currently remain on treatment pending response evaluation. In the co-mutated cohort, only 4 received both A + ET and E, (3 received A first, 1 received E first). Pts treated with A + ET only (n=23) had a median time to next treatment (mTTNT) of 120 days (range 5-566) and those who received E only (n=8) had a mTTNT of 86 days (range 13-106) (Chi square=4.289, df = 1, p<0.05). The 4 pts who received both therapies were excluded from this mTNNT analysis. Conclusions: The rate of ESR1 and PIK3CA co-mutation in this cohort was consistent with the reported literature. mTTNT was significantly longer with A + ET compared to E, but real world outcomes on E remain immature with one-third of pts still on E at the time of analysis. A limitation of this study was the small sample size. Further analyses are warranted to clarify the optimal sequencing of these targeted therapies such as A, E, and capivasertib in pts with co-mutations in ESR1 and PIK3CA.
Frequency of dose reductions of abemaciclib in metastatic and early-stage hormone positive, HER2 negative breast cancer.
Authors: Ter-Zakarian Anna , Donovan Lauren N. , Nasraty Farah
Published: June 2024

e13099

Background: Abemaciclib is a CDK4/6 inhibitor which in combination with endocrine therapy (ET) improves progression-free survival in hormone receptor (HR)-positive, HER2 negative advanced breast cancer, as well as invasive disease free-survival in high-risk early-stage breast cancer. However, abemaciclib is associated with adverse events which may limit treatment adherence. In this single-center study, we describe real-world safety outcomes of early-stage and advanced HR-positive, HER2 negative breast cancer patients prescribed abemaciclib in conjunction with ET. Specifically, we analyze the frequency of adverse events and dose reductions (DR). Methods: We conducted a retrospective study of patients treated at Scripps Clinic between 1/1/2019-1/1/2023 with HR-positive, HER2 negative breast cancer prescribed abemaciclib with ET. Primary analyses were performed to discern clinical characteristic differences between groups. Categorical variables were summarized as frequencies and compared between arms by Chi-Square tests or Fisher’s Exact Tests. All continuous variables were summarized as means and standard deviations and compared between arms by T-Tests if normally distributed or summarized as medians and compared between arms by Mann-Whitney Tests otherwise. Statistical significance was set to 0.05 and all analyses were conducted in R. Results: A total of 77 patients were analyzed including 62% in the adjuvant setting and 38% in the metastatic setting. 51% of patients required DR. Patients requiring DR were older relative to those not requiring DR (59 vs 52 years of age, p=0.019). Those requiring DR remained on abemaciclib longer relative to those without DR (509 vs 350 days, p=0.057). Among those requiring DR, there were higher rates of grades II-IV diarrhea (p<0.001) and Loperamide use (p=0.083). Those requiring DR also had higher rates of neutropenia (54% vs 29%, p=0.027), abdominal cramping (39% vs 8%, p=0.002), nausea (39% vs 13%, p=0.011), and fatigue (51% vs 32%, p=0.079). Among 9 patients who expired on abemaciclib, 7 were in the metastatic setting and 1 was linked to an adverse effect from abemaciclib; none required DR (24% vs 0%, p<0.001). Finally, patients in the adjuvant setting remained on abemaciclib longer relative to those in the metastatic setting (526 vs 281 days, p=0.01). 95% of patients experienced symptom improvement with DR (p<0.001). Conclusions: Our study describes real-world safety outcomes of patients with HR-positive, HER2 negative breast cancer treated with abemaciclib and ET. More than half of patients required DR. Those who reduced their abemaciclib dose had improvement of clinical symptoms and remained on therapy longer. Based on our findings and given the importance of adherence in treatment efficacy, a lower starting dose of abemaciclib may be a more tolerable strategy, especially among older patients who required more DR in our study.
Association between genetic susceptibility and mortality in triple-negative breast cancer.
Authors: Akpoviroro Ogheneyoma , Sauers Nathan Kyle , Uwandu Queeneth , Ekechukwu Ifunanya , Manyele Victoria , Castagne Myriam , Srinivasa Hema Malini , Sharma Namita
Published: June 2024

e13130

Background: We sought to determine if positive germline genetic tests in patients with triple negative breast cancer (TNBC) was associated with mortality. Methods: Retrospective review. Inclusion criteria: female, 18-85, stage 1-3 TNBC, 2010-2015; 5-year follow-up period from date of cancer diagnosis, or follow-up until death if sooner. Results: Out of the total population of 219 patients, 37.9% (83/219) underwent genetic testing. All patients who underwent genetic testing were Caucasian; most were non-Hispanic (78/83, 94.0%). The average age of the population of patients who underwent genetic testing was 49.6; there were no differences in age between those with a positive genetic test (PT) versus(vs) a negative genetic test (NT) (p=0.963). The average ECOG score was 0.2 and this was similar between the PT and NT groups (p=0.725). The average tumor size was 25.3 and this was similar between PT and NT groups(p=0.992). Among those who underwent testing, a PT was observed in 22.9% (19/83) and a NT in 77.1% (64/83). Within the PT group, 15.8% (3/19) experienced recurrent disease, while 18.8% (12/64) in the NT group experienced recurrent disease (p=1.000).Within the PT group, 5.3% (1/19) were deceased compared with 28.1% (18/64) in the NT group (p=0.590). When recurrent versus nonrecurrent disease was compared regardless of genetic test results, 73.3% (11/15%) in the recurrence group were deceased, compared with 11.8% (8/68) in the non-recurrence group (p<0.001). When the genetic test population was stratified by recurrence, there was no association between genetic test results and living status in recurrent disease (p=0.154), or non-recurrent disease (p=0.183). Conclusions: Most patients who underwent genetic testing were Caucasian, and the average age of the cohort was approximately 49 years. Otherwise, the demographic characteristics were comparable between patients with a positive genetic test and those with a negative genetic test. Positive genetic test results were not associated with recurrent TNBC, or tumor size. However, the presence of recurrence was associated with a higher incidence of mortality, irrespective of genetic test results. Our study shows that genetic susceptibility to breast cancer was not associated with greater mortality. More has to be done to determine if racial disparities occur in offering genetic testing to racial minorities who meet criteria.
A propensity-matched cohort study of neoadjuvant immunotherapy combined with chemotherapy versus neoadjuvant chemotherapy for early-stage triple-negative breast cancer.
Authors: Zheng Chunhui , Wang Yongsheng , Qi Yingxue , Song Yunjie , Yin Xiangyu , Luo Ningning
Published: June 2024

e13134

Background: Preferred neoadjuvant treatment (NAT) regimens for early-stage triple-negative breast cancer (TNBC) include anthracycline-cyclophosphamide and taxane-based chemotherapy. This study compared the efficacy, safety and biomarker exploration of camrelizumab combined with chemotherapy and chemotherapy as neoadjuvant treatment for early-stage TNBC. Methods: This study included 2 cohorts with different NAT regimens, matched (2:1) according to age, clinical T and N stage, and Ki-67 status. Patients in the immune combination chemotherapy (NIC) cohort were recruited from a phase II clinical trial (NCT04676997). NIC patients received intravenous camrelizumab at a dose of 200mg and simultaneous chemotherapy consisted of platinum-free drugs, or platinum containing drugs. Patients in the neoadjuvant chemotherapy (NAC) cohort regimen comprised 4 cycles of paclitaxel 175 mg/m2, and 4 cycles of epirubicin (90 mg/m2, d1, q2w) + cyclophosphamide (600 mg/m2, d1, q2w). The indicators of this study include pCR, breast pCR (bpCR), axillary lymph node dissection (ALND) rate, breast conserving surgery (BCS) rate and tumor immune microenvironment (TIME) analysis of gene expression profiling. Results: Of 252 eligible patients, 162 patients were identified in the analysis after propensity score matching (PSM). Compared with NAC alone, the addition of camrelizumab brought higher pCR rates (64.81% versus 37.04%, p<0.05), ALND rates (38.89% versus 12.96%, p<0.05) and comparable BCS rates (20.37% versus 15.74%, p<0.05). Gene expression analysis was performed on tumor tissue samples from 12 patients receiving NAC and 16 patients receiving NIC before and after NAT. The results showed that the TIME status of the NIC and NAC groups before treatment was basically the same. Moreover, we respectively compared the TIME status of patients with pCR and non_pCR in NIC and NAC before NAT. The results found that there were 9 significantly different signatures (p<0.05) between pCR and non_pCR patients in the NIC group, and 1 signature (p<0.05) in the NAC group, respectively. Notably, we found 8 signatures (B Cells, CD8 T Cells, TIS, IFN Gamma, Lymphoid, T Cell, APM, Immunoproteasome), that were scored significantly higher only in pCR patients in the NIC group compared with non-pCR patients, and 8 signatures could promote response to immunotherapy. The common difference signature between the two groups is Treg cells. Conclusions: In patients with early-stage TNBC, neoadjuvant treatment with camrelizumab plus chemotherapy significantly improved pCR with an acceptable safety profile. Differences in TIME may affect response to treatment regimens. Future validation in prospective randomized controlled trials with larger sample sizes is needed. Clinical trial information: NCT04676997 .
Unveiling the complexity: Liquid biopsy-based proteomic exploration of triple-negative breast cancer in women.
Authors: Zuccari Debora Aparecida Pires de Campos , Tamarindo Guilherme , Novais Adriana Alonso , Frigieri Barbara Maria , da Silveira Juliano Coelho , de Souza Fabiana Ferreira , Labate Carlos Alberto , Chuffa Luis Gustavo de Almeida
Published: June 2024

e13138

Background: This groundbreaking study places a spotlight on breast cancer in women, with a specific emphasis on the challenging triple-negative breast cancer (TNBC) subtype. Delving into the intricate world of extracellular vesicles (EVs) from TNBC-diagnosed individuals, the research meticulously compares various conditions, including healthy controls, benign tumors, recurrent tumors, and those in remission. Employing cutting-edge techniques like liquid biopsy and LC-MS/MS, the study meticulously explores the proteomic profile of serum exosomes, aiming to pinpoint diagnostic and prognostic markers in breast cancer. Methods: In the initial phase, EVs were expertly isolated and characterized from blood plasma samples exclusively from women, utilizing state-of-the-art methods such as ultracentrifugation and nanoparticle tracking analysis (NTA). Despite applying rigorous statistical criteria, the study found no significant differences in EV concentrations and sizes among the diverse groups. However, the ensuing proteomic analysis uncovered 130 proteins, with Cystatin A and Histone H2A emerging as promising biomarkers for TNBC. To validate them, the study intricately tested tumor cell lines from distinct subtypes, representing luminal, triple-negative, and HER2 overexpressed. The examination of gene and protein expression through RT-qPCR and western blotting added a layer of depth to the research, unraveling the complexity of regulatory processes within cells and demonstrating a remarkable congruence between protein levels found in the proteomics from patients’ serum and in immortalized cell lines. Results: The proteomic analysis brought to light the absence of CSTA and HIST1H2A expression in benign tumor patients, varied levels in malignant tumor patients, and a substantial increase in TNBC patients pre-mastectomy. Validating these findings through western blotting further accentuated the potential of these proteins as distinguishing factors. Conclusions: In conclusion, this pioneering study not only underscores the immense potential of liquid biopsy-based proteomic analysis in identifying crucial diagnostic and prognostic markers in breast cancer but also sheds light on the intricate nuances of the challenging TNBC subtype. Our findings unveil valuable insights that pave the way for future personalized treatment strategies, marking a significant stride forward in breast cancer research.