tbuckley/cabot-search huggingface dataset:
Employing semi-quantitative methods to classify breast cancer markers (ER, PR, HER2, Ki67) expression, using the RT-qPCR based APIS Breast Cancer Subtyping Kit.
Authors: Anna Gasior, Anne-Sophie Wegscheider, Jack Paveley, Kimberly Jane Howard, Mathew Harrison, Leanne Gough, Joanna Gorniak, Sara Rollinson, Zoe Pounce, Axel Niendorf
Journal: Journal of Clinical Oncology (2024)

e13091 Background: Accurate determination of breast cancer (BC) biomarker status is crucial for guiding patient management decisions. Histopathologists commonly use semi-quantitative scoring systems to convert subjective observations of immunohistochemistry (IHC) marker expression into quantitative data, allowing a more detailed categorisation of marker status. The APIS Breast Cancer Subtyping Kit (BCSK) is an in vitro diagnostic test, detecting the relative expression of seven mRNA target genes ( ESR1, PGR, ERBB2, MKI67, CCNA2, PCNA, and KIF23) from invasive BC tissue. The APIS BCSK reports a positive/negative result for each biomarker alongside a molecular classification. Here, we demonstrate that by implementing additional RNA expression cut-off values, it is possible to generate a semi-quantitative result by further stratifying target expression into negative, low, medium, and high status using the APIS BCSK. Methods: 368 formalin-fixed paraffin-embedded (FFPE) samples of BC cases were used, obtained by core needle biopsy or resection. IHC scores were correlated with copy numbers as determined by an independently validated digital PCR (dPCR) assay and were used to set copy number cut-off values corresponding to IHC classification. The generated dPCR cut-off values were used to evaluate the corresponding ∆Ct values (RNA expression results derived from the APIS BCSK). For each target, three ΔCt cut-offs were established, facilitating classification into negative, low, medium, and high expression. Results: The semi-quantitative approach successfully classified target expression levels ( ESR1, PGR, ERBB2, MKI67). Overlap in ΔCt values was observed in central IHC categories for all targets, likely due to tumor heterogeneity and differing measurement methods for IHC and RT-qPCR. Despite these discrepancies, the derived cut-off values define a semi-quantitative scale for each target (Table). Conclusions: This study has established a methodology that utilises target copy number values and IHC protein quantification to establish ΔCt cut-off points. For each target we have defined four distinct groups as negative, low, medium, and high expression. This approach provides a semi-quantitative scale for evaluating each target with the APIS BCSK and serves as a valuable tool for classifying and understanding target expression levels. [Table: see text]
Evolution of germline <i>BRCA1/2</i> testing practices: A five-year comparative analysis among oncology providers and patients.
Authors: Doreen Effange, Robert Richard Buras, Kelly C. Gast, Joy Larsen Haidle, Lillie D. Shockney, Rachel Lynn Yung, Kimberly Demirhan, Molly Kisiel, Elana Plotkin
Journal: Journal of Clinical Oncology (2024)

e13172 Background: The Association of Cancer Care Centers (ACCC) launched a quality improvement initiative in 2018 to address suboptimal germline BRCA1/2 testing rates and identify barriers impeding testing for patients with early-stage or metastatic breast cancer. Between 2018 and 2023, changes in clinical guidelines led to expanded testing criteria and increased referrals for genetic testing. A follow-up survey in 2023 aimed to assess changes in testing practices and challenges faced by cancer care teams, considering the evolving landscape of genetic testing and the impact of the COVID-19 pandemic. Methods: In 2018, a survey of 95 oncology providers was conducted to explore provider characteristics, testing characteristics, and challenges/barriers to germline BRCA 1/2 testing. The survey was conducted again in 2023 for comparative analysis with a response of 115 oncology providers. The surveys explored provider characteristics, testing practices, and challenges/barriers to germline BRCA1/2 testing. To comprehensively understand the patient's perspective, an additional survey was conducted in October 2023, involving 61 individuals recently diagnosed with breast cancer to evaluate the patient experience with germline BRCA 1/2 testing and subsequent follow-up. Results: The adoption of expanded testing criteria, which influenced changes in clinical guidelines, has led to a substantial increase in referrals for genetic testing. The utilization of genetic testing by medical oncologists experienced a notable surge with 64% of survey respondents in 2023 reporting that medical oncologists most often initiated tests for germline BRCA1/2 mutations, compared to 29% in 2018. Patients’ awareness and engagement were high, with 82% undergoing germline BRCA1/2 testing, 48% undergoing testing at diagnosis, 33% before treatment, and 13% during treatment. In 2023, 23% of providers reported routinely ordering germline BRCA1/2 testing for patients with early-stage breast cancer, marking a threefold increase from the 2018 survey results. For patients with metastatic breast cancer, 41% of providers routinely ordered BRCA mutation testing, a threefold increase from 14% in 2018. While testing rates improved, challenges and barriers persist such as patient concerns (47%), access to genetic counselors (42%), turnaround time for test results (36%), and reimbursement issues (28%). Conclusions: The comparative analysis revealed a moderate improvement in germline BRCA1/2 testing practices, with increased provider engagement and patient awareness. Despite progress, challenges persist, needing multi-pronged efforts to enhance testing uptake and distribute critical information on testing to patients. The results indicate positive trends but underscore the importance of addressing barriers for comprehensive patient care.
Analysis of regulation of cell death pathway genes in CSC-enriched TNBC after treatment with doxorubicin: A potencial biomarker.
Authors: Warne Pedro Andrade, Isabela Nery Tavares Barbosa, Luciana Maria Silva, Milene Pereira Moreira
Journal: Journal of Clinical Oncology (2024)

e13154 Background: Breast cancer is one of the most common cancers in women worldwide, and triple-negative breast cancer (TNBC) accounts for approximately 10-20% of all cases globally. TNBC has the worst prognosis among other types of breast cancer due to the lack of targeted therapy. In addition, TNBC tumors exhibit significant cellular and molecular heterogeneity, along with the presence of cells with cancer stem cell (CSC) characteristics, which contribute to the low response to available chemotherapy treatments, leading to chemoresistance, recurrence and metastasis. objective of this study is to evaluate the expression of genes related to cell death and survival pathways in CSCs-enriched spheroids DOX-treated obtained of BT-549 cells, a human TNBC cell line. The death receptor genes include TNFRSF10B, TNFRSF10C, CFLAR, RIPIK1, CASP8, NFKB1, RELA, and MLKL. Methods: To achieve this, gene expression was analyzed through RT-qPCR, comparing the expression in DOX-treated CSCs-enriched spheroids (IC50 55.7 μM/ 48h incubation) and untreated CSCs-enriched spheroids. Preliminary results indicated that, among the evaluated genes, only CFLAR, NFKB1, and RELA were expressed in the untreated CSCs-enriched spheroids, while the others were not expressed under any condition. Results: The genes CFLAR, NF- κ B and RELA showed considerable Ct values, while the remaining genes did not exhibit a Ct value in one or more samples. The gene CFLAR showed an overexpression, both in monolayers vs. spheroids and in treated spheroids vs. untreated spheroids, which can be related to the inhibition of Caspase 8 and consequently, the apoptotic activity of cells. The overexpression of the RELA, same as CFLAR, suggests increased inflammation pathway activation in the tumor microenvironment. However, the lower expression of the NF-κB1 gene in treated spheroids vs. untreated spheroids may be related to the production of ROS, suppressing its activation. Conclusions: The expression of NFKB1 and RELA genes is associated with the cellular survival pathway, which may be linked to the resistance to the drug observed in many patients. Previous studies of our group have shown that achieving a satisfactory result of DOX action on CSCs-enriched spheroids requires using a dose 100 times higher than that used in monolayer cells. This may be related to the non-expression of the TNFRSF10B, TNFRSF10C, RIPIK1, CASP8, and MLKL genes in CSCs-enriched spheroid DOX-treated. Thus, the results obtained so far indicate that DOX may have an impact on the expressed genes in CSCs-enriched spheroids and demonstrate the expression of apoptosis inhibitors in treated breast spheres. Consequently, the expression of these genes in BT-549 cells TNBC indicates a pro-inflammatory, anti-apoptotic, and pro-cell survival profile of CSC-enriched spheroids.
Treatment patterns of adenoid cystic carcinoma of the breast: A systematic review.
Authors: Jonathan Macias, Felipe Sales Nogueira Amorim Canedo, Shou-En Lu, Chunxia Chen, Caio Teixeira Heleno, Matthew Bridgeman, Priscila Hermont Goncalves, Mridula Annette George
Journal: Journal of Clinical Oncology (2024)

e13147 Background: Adenoid cystic carcinoma of breast (ACC-B) is a rare subtype of breast cancer (BC) accounting for 0.1% of all BCs. It shares histologic features with ACCs arising in the salivary glands and other locations. Given the hormone receptor (HR) negative phenotype [negative expression of the estrogen receptor (ER), progesterone receptor (PR)], some clinicians treat ACC-B as a basal subtype of BC, which is predominantly treated with chemotherapy. However, ACC-B has a more indolent and favorable clinical behavior. There are no established treatment guidelines for ACC-B. We conducted a systematic review of the literature on the treatment patterns for ACC-B. Methods: We followed the PRISMA criteria using the database in Cochrane, Embase, PubMed, Scopus, and Web of Science. The Covidence software was used for screening and data extraction. Eligible studies discussed the management of stage I-III ACC-B from 1960 to 2022. Individual patient (pt) demographics, tumor characteristics, treatment and outcomes were collected, when available. Results: The database search found 2864 studies, of which 187 articles met the inclusion criteria in the study protocol. Given the rarity of this subtype of BC, most studies were case reports (n=104). A total of 4370 pts with a median age of 57 years were eligible for analysis. Information on ER, PR and HER2 status was not available for all cases. For the cases in which this was reported, most were ER and/or PR negative (76% ER negative and 83% PR negative). Surgery was the primary treatment reported for 3984 pts. A total of 21.5% underwent mastectomy, 40.7% lumpectomy and 37.7% were treated with other modalities of surgery. In the group of patients for which information was available regarding the receipt of systemic therapy (n=3147), 82% did not receive neoadjuvant or adjuvant chemotherapy. Metastatic disease was reported to have developed in 2.2% of the total patients (n=98). Median time to recurrence was 31 months (0-460) with a median overall survival of 134 months (1-462). The most common site of metastases were the lungs (60%). Among the patients who developed metastatic disease and for whom initial treatment information was available; radiation was given to 32 pts, 26 received adjuvant chemotherapy and 15 received both radiation and chemotherapy. No patients that developed metastatic disease received neoadjuvant chemotherapy. Conclusions: Our results suggests that ACC-B has a clinical behavior different from basal subtype of BC. In our review, only 2.2% of pts relapsed with metastatic disease, even though most of the pts did not receive prior systemic therapy. We need to better understand the genomic landscape of ACC-B, to identify pts who may be at risk for recurrence and develop specific guidelines to treat this rare type of BC.
Efficacy and safety of eribulin plus gemcitabine in second-line or beyond for patients with HER2-negative metastatic breast cancer (MBC): A multicenter, open-label, single-arm, phase II study.
Authors: Peijian Peng, Xiaolu Xu, Jincai Zhong, Jin-Hui Ye, Zhi-Hui Wang, Hong Wang, Hong Lin, Caiwen Du, Guorong Zou, Jie Ouyang, Ying-ying Shi, Fei Xu, Gengsheng Yu, Yongkui Lu, Yong-Xia Wang, Shi-En Cui, Lu-Zhen Li
Journal: Journal of Clinical Oncology (2024)

e13139 Background: The combination of eribulin and gemcitabine has demonstrated a similar progression-free survival (PFS) benefit as paclitaxel plus gemcitabine, with less neurotoxicity, for patients with MBC who have not received prior cytotoxic chemotherapy. However, the effect of eribulin plus gemcitabine on PFS in second line or beyond remains unclear. Methods: This open-label, single-arm, phase II study (NCT05263882) was conducted at 14 institutions in China. Eligible patients had histologically confirmed HER2-negative MBC and had received at least one prior taxane-containing chemotherapy regimen for advanced disease, and anthracycline-containing regimens in the adjuvant setting. Patients received intravenous infusions of eribulin (1.4 mg/m 2 ) and gemcitabine (1.0 g/m 2 ) on days 1 and 8 of a 21-day cycle. Efficacy outcomes, including PFS, objective response rate (ORR), and disease control rate (DCR), were assessed using RECIST v1.1. Adverse events (AEs) were graded according to NCI-CTC version 5.0. Results: A total of 70 patients were enrolled from November 2021 to October 2023; 47 (71.4%) had HR+HER2- and 18 (28.6%) had triple-negative MBC. The median patient age was 50 years (range: 31-68), and the sites of metastasis were the bone (68.6%), liver (52.9%), lymph nodes (48.6%), lung (44.3%) and brain (10.0%). Patients had received a median of 3 prior lines of systemic treatment, 2 lines of chemotherapy, and 1 line of endocrine treatment. Among all patients, the ORR was 48.6%, the DCR was 92.9% and the median PFS was 7.2 months. For the HR-positive subgroup, the median PFS was 8.4 months, while for the triple-negative subgroup, it was 6.3 months. Among HR+ patients who had received prior CDK4/6 inhibitor treatment, the median PFS was 7.2 months. In the subgroup of HR+ patients who had not received CDK4/6 inhibitor treatment, the median PFS had not been reached. For the HR+ HER2-low subgroup, the median PFS was 8.4 months. The most common grade 3-4 AEs were hematological, including neutropenia (38.6%), leukopenia (31.4%), anemia (24.3%), and thrombocytopenia (15.7%). Grade ≥3 perceived AEs were relatively low. Conclusions: Eribulin plus gemcitabine was effective in heavily pretreated patients with HER2- MBC, while maintaining a predictable and manageable safety profile. Clinical trial information: NCT05263882 . [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: Ting Xu, Lili Zhang, Yuan Yuan, Sainan Hu, Min Dong, Xinyu Xu, Jiayuan Huang, Weili Xiong, Kexin Lou
Journal: Journal of Clinical Oncology (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.
Association between GPRC5A expression and carboplatin efficacy in triple-negative breast cancer patients.
Authors: Lei Li, Jinhai Tang, Honglei Zhou
Journal: Journal of Clinical Oncology (2024)

e13142 Background: Triple-negative breast cancer (TNBC) patients often face a grim prognosis, primarily due to their resistance to chemotherapy. Carboplatin is a common treatment for TNBC, particularly effective in BRCA1/2 mutations, but its efficacy varies in BRCA1/2 wild-type patients. A previous study identified GPRC5A expression as a biomarker for carboplatin chemotherapy in ovarian cancer, yet its association with carboplatin efficacy in TNBC remains unknown. This study aims to investigate whether GPRC5A can serve as a biomarker for predicting carboplatin efficacy in TNBC and to elucidate the underlying mechanisms. Methods: Analyzing clinical data from the past 5 years in Division of Breast &amp; Thyroid Surgery in Jiangsu Province Hospital, we identified 199 TNBC patients treated with carboplatin. GPRC5A expression in TNBC tumors was assessed via immunohistochemistry (IHC) and evaluated by three individual pathologists. Expression levels were categorized as low (low), low (mild), high (moderate), and high (high). The Chi-square test was employed to assess the correlation between GPRC5A expression and carboplatin efficacy. TNBC-derived organoids were used to validate the relationship between GPRC5A expression and carboplatin sensitivity. Results: Among the 199 TNBC patients, 31 (17.2%) had BRCA1/2 mutations. The pathologic complete response (pCR) rate in BRCA1/2 mutation patients receiving carboplatin was 83.9%, compared to 61.3% in BRCA1/2 wild-type patients (p=0.016). Analyzing the relationship between GPRC5A expression and BRCA1/2 gene mutations in 145 patient samples revealed no significant association (p=0.37). Irrespective of BRCA1/2 mutation status, patients with low/mild GPRC5A expression had a higher pCR rate (74.1%) compared to those with moderate/high GPRC5A expression (45%, p&lt;0.001). TNBC-derived organoids treated with carboplatin showed a cell survival rate of 31.25% (±8.5%) in low GPRC5A expression organoids and 56.25% (±12.6%) in high GPRC5A expression organoids (p=0.017). Conclusions: Our study demonstrates a correlation between GPRC5A expression and BRCA1/2 mutation status in TNBC. Furthermore, TNBC patients with low GPRC5A expression exhibited a more favorable response to carboplatin treatment, suggesting GPRC5A could be a potential biomarker for predicting carboplatin efficacy in TNBC patients.
Real-world immune-related adverse events in patients with early triple negative breast cancer who received pembrolizumab.
Authors: Athira Jayan, Jasmine S Sukumar, Benjamin David Fangman, Tejal Amar Patel, Akshara Singareeka Raghavendra, Diane D. Liu, Ronald Rauch, Karen Basen-Engquist, Debashish Tripathy, Carlos Hernando Barcenas
Journal: Journal of Clinical Oncology (2024)

1099 Background: The addition of pembrolizumab to chemotherapy (KEYNOTE-522 regimen) in high risk early triple negative breast cancer (TNBC) has improved clinical outcomes. However, this treatment can result in immune-related adverse events (irAEs) involving any organ and in some cases, life-long toxicities or even death. This retrospective study describes real-world patterns of irAEs in patients (pts) with early TNBC who received pembrolizumab at two academic centers. Methods: We evaluated irAEs in pts with stage II-III TNBC from MD Anderson Cancer Center and Lyndon B Johnson diagnosed between January 2018 and May 2023 who received neoadjuvant pembrolizumab plus chemotherapy. We excluded those enrolled on clinical trials. We utilized ASCO irAE and CTCAE v5 guidelines for toxicity grading. Logistic regression assessed the effect of clinical variables on irAEs, adjusting for covariates. Results: We identified 233 pts with a median age of 51 ± 12 years; 62% with stage II and 35% with stage III TNBC; 25% were Hispanic/Latino, 21% non-Hispanic Black and 42% were non-Hispanic White. In total, 80 pts (34%) developed 100 separate irAEs (94 with definite and 6 with possible/probable attribution). The most common irAEs were endocrine (52%) followed by gastrointestinal (23%). Grade ≥ 3 irAE occurred in 26 instances, with the most common being gastrointestinal (13 instances). A fatal irAE occurred in 2 pts where both were colitis. A total of 26 irAEs resulted in hospitalization, 45 required systemic steroids, and 15 required additional immunosuppressive therapy. Most (66) irAEs were unresolved at last follow up, although the majority had improved to grade 1 (37/66) and 32 patients discontinued pembrolizumab early due to irAEs. No clinical factor (race, stage, tumor grade, age, body mass index) was associated with development of an irAE. Conclusions: In this real-world diverse population, we identified a similar rate and severity of irAEs as reported in the KEYNOTE-522 trial. Hospitalizations occurred in 26% of irAEs while most developed persistent immune toxicity. Gastrointestinal irAEs were more common compared to KEYNOTE-522 reported data. Research is needed to better predict and mitigate the burden of irAEs and to improve the long-term survivorship care of pts with early TNBC pts who receive pembrolizumab. [Table: see text]