tbuckley/cabot-search huggingface dataset:
Case-Case Genome-Wide Analyses Identify Subtype-Informative Variants that Confer Risk for Breast Cancer
Authors: Xiaohui Sun, Shiv P. Verma, Guochong Jia, Xinjun Wang, Jie Ping, Xingyi Guo, Xiao-Ou Shu, Jianhong Chen, Andriy Derkach, Qiuyin Cai, Xiaolin Liang, Jirong Long, Kenneth Offit, Jung H. Oh, Anne S. Reiner, Gordon P. Watt, Meghan Woods, Yaohua Yang, Christine B. Ambrosone, Stefan Ambs, Yu Chen, Patrick Concannon, Montserrat Garcia-Closas, Jian Gu, Christopher A. Haiman, Jennifer J. Hu, Dezheng Huo, Esther M. John, Julia A. Knight, Christopher I. Li, Charles F. Lynch, Lene Mellemkjær, Katherine L. Nathanson, Barbara Nemesure, Olufunmilayo I. Olopade, Andrew F. Olshan, Tuya Pal, Julie R. Palmer, Michael F. Press, Maureen Sanderson, Dale P. Sandler, Melissa A. Troester, Wei Zheng, Jonine L. Bernstein, Matthew F. Buas, Xiang Shu
Journal: Cancer Research (2024)

Abstract Breast cancer includes several subtypes with distinct characteristic biological, pathologic, and clinical features. Elucidating subtype-specific genetic etiology could provide insights into the heterogeneity of breast cancer to facilitate the development of improved prevention and treatment approaches. In this study, we conducted pairwise case–case comparisons among five breast cancer subtypes by applying a case–case genome-wide association study (CC-GWAS) approach to summary statistics data of the Breast Cancer Association Consortium. The approach identified 13 statistically significant loci and eight suggestive loci, the majority of which were identified from comparisons between triple-negative breast cancer (TNBC) and luminal A breast cancer. Associations of lead variants in 12 loci remained statistically significant after accounting for previously reported breast cancer susceptibility variants, among which, two were genome-wide significant. Fine mapping implicated putative functional/causal variants and risk genes at several loci, e.g., 3q26.31/TNFSF10, 8q22.3/NACAP1/GRHL2, and 8q23.3/LINC00536/TRPS1, for TNBC as compared with luminal cancer. Functional investigation further identified rs16867605 at 8q22.3 as a SNP that modulates the enhancer activity of GRHL2. Subtype-informative polygenic risk scores (PRS) were derived, and patients with a high subtype-informative PRS had an up to two-fold increased risk of being diagnosed with TNBC instead of luminal cancers. The CC-GWAS PRS remained statistically significant after adjusting for TNBC PRS derived from traditional case–control GWAS in The Cancer Genome Atlas and the African Ancestry Breast Cancer Genetic Consortium. The CC-GWAS PRS was also associated with overall survival and disease-specific survival among patients with breast cancer. Overall, these findings have advanced our understanding of the genetic etiology of breast cancer subtypes, particularly for TNBC. Significance: The discovery of subtype-informative genetic risk variants for breast cancer advances our understanding of the etiologic heterogeneity of breast cancer, which could accelerate the identification of targets and personalized strategies for prevention and treatment.
Overall survival with palbociclib (PAL) plus an aromatase inhibitor (AI) versus AI alone in older patients (pts) with de novo, HR+/HER2− metastatic breast cancer: A SEER-Medicare analysis.
Authors: Adam Brufsky, Rickard Sandin, Stella Stergiopoulos, Connie Chen, Siddharth Karanth, Benjamin Li, Lizzi Esterberg, Doris Makari, Sean D. Candrilli, Ravi K. Goyal, Hope S. Rugo
Journal: Journal of Clinical Oncology (2024)

1111 Background: Cyclin-dependent kinase 4/6 inhibitor in combination with endocrine therapy (CDK4/6i) is the current standard of care in first line (1L) treatment for hormone receptor–positive and human epidermal growth factor receptor 2-negative (HR+/HER2–) metastatic breast cancer (mBC). Comparative effectiveness evidence assessing overall survival (OS) outcomes are limited, particularly in older pts. Our primary objective was to compare OS in Medicare pts treated with 1L PAL + AI versus AI alone in the current SEER dataset. Methods: We conducted a retrospective analysis of HR+/HER2–mBC pts using the SEER-Medicare database. Medicare-enrolled pts aged ≥65 years diagnosed with de novo HR+/HER2– mBC between February 1, 2015, and December 31, 2019 were included. Pts were followed from the start of 1L therapy line until death, Medicare disenrollment, enrollment in a health maintenance organization plan, or the end of available study follow-up (December 31, 2020), whichever came first. Stabilized inverse probability of treatment weighting (sIPTW) was the primary method used to balance patient characteristics at baseline, with propensity score matching (PSM) and multivariable CPH regression as sensitivity analyses. Median OS and the hazard ratio (HR) were estimated using the weighted Kaplan-Meier (KM) method and the weighted Cox proportional hazard (CPH) regression model, respectively. Results: Of 779 included pts, 296 received PAL+AI and 483 received AI alone. Median follow-up was 23.9 months for the PAL+AI arm and 18.2 months for the AI alone arm. After sIPTW adjustment, median OS was 37.6 months (95% CI=34.8-42.0) for PAL+AI vs 25.5 months (95% CI=22.0-28.9) for AI alone (HR=0.73, 95% CI=0.59-0.91). Results from the PSM and CPH regression analyses were consistent with the primary analysis. Key patient characteristics are presented (Table). Conclusions: This comparative effectiveness study showed that PAL+AI was associated with significantly prolonged OS vs AI alone in the 1L treatment of older pts with de novo HR+/HER2- mBC treated in US clinical practice using the SEER-Medicare database. Our results add to the body of evidence on the survival benefit of PAL+AI in this population. [Table: see text]
Interim analysis (IA) of the giredestrant (G) + everolimus (EVERO) arm in MORPHEUS Breast Cancer (BC): A phase I/II study of G treatment (tx) combinations in patients (pts) with estrogen receptor-positive (ER+), HER2-negative, locally advanced/metastatic BC (LA/mBC).
Authors: Seth Andrew Wander, Salomon M. Stemmer, Hope S. Rugo, Seock-Ah Im, Peter Kar Han Lau, Shani Paluch-Shimon, Clélia Cahuzac, Annie Collier, Mona D. Shah, Huy X. Ngo, Richard B. Schwab, Jing Zhu, Mafalda Oliveira
Journal: Journal of Clinical Oncology (2024)

1059 Background: Endocrine therapy (ET) + a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) is a therapeutic mainstay for first-line tx of ER+ mBC. Finding effective ET combinations after progression remains a challenge; however, targeting the Akt/mTOR pathway is a promising approach. G is a highly potent, non-steroidal, oral (PO), selective ER antagonist and degrader that is well tolerated and achieves robust ER occupancy. EVERO is an approved mTOR inhibitor. Here, we present a 16-week IA of the G + EVERO arm in MORPHEUS BC (NCT04802759). Methods: Eligible pts with disease progression on 1–2 lines of ET (including a CDK4/6i) for LA/mBC were randomized 1:6 to receive G (30 mg PO daily [QD]) or G + EVERO (10 mg PO QD) until disease progression (PD)/unacceptable toxicity. The study was not designed to make explicit power and type I error considerations for a hypothesis test. Primary endpoints were safety and objective response rate (ORR); other endpoints included progression-free survival (PFS), overall survival, clinical benefit rate, disease control rate (DCR), duration of response, and pharmacokinetics. Steroid mouthwash was recommended for prophylaxis or treatment. Genetic alterations were defined using baseline circulating tumor DNA. Results: Results for the G arm have been presented previously and are not included here. As of July 24, 2023, 15 pts were enrolled in the G + EVERO arm: 66.7% and 33.3% received 1–2 prior lines of therapy for LA/mBC, respectively; 26.7% had prior fulvestrant, and 73.3% had liver metastasis at enrollment. One pt had prior capecitabine. Safety data are in the table. Confirmed ORR in the G + EVERO arm was 26.7% (n = 4). Partial responses were reported in 26.7% of pts (n = 4; all had ESR1 mutations, 1 also had an Akt pathway mutation), 46.7% of pts (n = 7) had stable disease, and the DCR was 53.3% (n = 8). Median PFS was not reached at data cutoff. No clinically relevant drug–drug interactions were observed. Conclusions: Safety of G + EVERO was aligned with the individual safety profile of each drug with no overlapping toxicities or new safety signals seen. An encouraging efficacy signal was observed with G + EVERO in pts with PD on 1–2 lines of ET (including a CDK4/6i). G + EVERO is being further investigated in the Phase III evERA BC trial (NCT05306340). Clinical trial information: NCT04802759 . [Table: see text]
The role of epithelial-mesenchymal transition markers in invasive breast cancer among patients of Arab descent.
Authors: Mais Salleh, Waed Alkaram, Fadi Zaiem, Mira Kheil, Deepti Jain, Marya Wahidi, Julie Boerner, Hyejeong Jang, Seongho Kim, Robert Morris, Sudeshna Bandyopadhyay, Rouba Ali-Fehmi
Journal: Journal of Clinical Oncology (2024)

e13166 Background: Epithelial-mesenchymal transition (EMT) is the process wherein polarized and cohesive epithelial cells lose their epithelial characteristics and acquire a mesenchymal phenotype and proceed to the invasive form of the tumor. Numerous regulators play a role in the complex signaling pathways that mediate the EMT process. This study aims to investigate the immunohistochemical (IHC) expression of several EMT-related markers and their implications on the diagnosis and prognosis of breast cancer in a cohort of Arab descent women. Methods: Patients of Arab descent treated surgically for invasive and in-situ breast cancer between 2017-2020 were included in the study. Expressions of Ki-67, Transforming growth factor- β (TGF-β), NF-kappaB (NF-kB), Snail, Vimentin, E-cadherin (E-Cad), and B-catenin (B-Cat) were evaluated by IHC in tissue microarray slides, as per guidelines in the literature. We examined the association between the tumor markers and other clinicopathological variables and prognosis. Fisher's exact tests were utilized to compare categorical variables between groups. Results: One hundred eleven patients were included, 65.8% had invasive ductal carcinoma (IDC); 19.8% had invasive lobular carcinoma (ILC); 13.5% had both ductal and lobular features, and 0.9% had ductal carcinoma in situ. 91 (54.1%) were grade 2 and 303 (41.4%) were grade 3 tumors. Most tumors were ER positive (81.8%), PR positive (75.7%), and HER-2 negative (77.5%). The median age at diagnosis was 52 years. High TGF- β expression was associated with higher frequency of grade 3 tumors (p=0.036), AJCC stage III (p=0.042), and larger tumor size (p=0.036) compared to those with low TGF-B expression. Patients with positive B-Cat expression had a higher risk of death compared to those with negative B-Cat expression (HR, 3.90; 95% CI, 1.19 to 15.93; p=0.024). IDC had a statistically significant increased expression of TGF-B (69.9% vs.45.5%, p=0.045), E-Cad (76.7% vs. 13.6%, p&lt;0.001), and B-Cat (P 39.7% vs. 0%, p&lt;0.001) when compared to ILC. The overall survival at 1 and 5 years were 96.3% (95% CI, 92.7-99.9) and 81.7% (95% CI, 73.8-90.3), respectively. Conclusions: Tumors with high expression for TGF- β and B-Cat exhibit more aggressive clinical behavior, suggesting the potential prognostic and therapeutic value of these markers. Due to the limited research focused on Arab descent women, findings from this study may provide the foundation for more extensive molecular and clinical studies to assess the validity and clinical utility of these biomarkers in breast cancer patients from diverse ethnic backgrounds.
A propensity-matched cohort study of neoadjuvant immunotherapy combined with chemotherapy versus neoadjuvant chemotherapy for early-stage triple-negative breast cancer.
Authors: Chunhui Zheng, Yongsheng Wang, Yingxue Qi, Yunjie Song, Xiangyu Yin, Ningning Luo
Journal: Journal of Clinical Oncology (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&lt;0.05), ALND rates (38.89% versus 12.96%, p&lt;0.05) and comparable BCS rates (20.37% versus 15.74%, p&lt;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&lt;0.05) between pCR and non_pCR patients in the NIC group, and 1 signature (p&lt;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 .
Coping with inter-observer variability when assessing AI for scoring of HER2-stained whole slides.
Authors: Florian Thomas, Denys Pommeret, Emmanuelle Guinaudeau, Bruno Poulet, Yahia Salhi, Jérôme Chetritt
Journal: Journal of Clinical Oncology (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.
Genomic alterations (GA) in ESR1, PIK3CA, AKT1, and PTEN in HR(+)HER2(-) patients (pts) with metastatic breast cancer (MBC): Co-occurrence and prevalence along treatment course.
Authors: Manali A. Bhave, Julia Quintanilha, Jeffrey S. Ross, Ryon P Graf, Mia Alyce Levy, Kevin Kalinsky
Journal: Journal of Clinical Oncology (2024)

1060 Background: The standard of care for HR(+) HER2(-) MBC is evolving with new biomarker-guided drugs, including novel selective estrogen receptor degraders (SERDs) for pts with ESR1 mutations (mut) and PIK3CA and AKT inhibitors for pts with alterations in the PI3K pathway (PIK3CA, AKT1, and PTEN). This study aimed to evaluate the co-occurrence and the prevalence of these GA in different metastatic lines of therapy in real-world practice for MBC. Methods: This study included pts with HR(+) HER2(-) MBC who underwent genomic testing using Foundation Medicine tissue or liquid comprehensive genomic profiling assays, with specimens collected within 60 days of therapy initiation. Clinical data were obtained by the nationwide (US-based) de-identified Flatiron Health and Foundation Medicine real-world clinicogenomic breast cancer database (FH-FMI CGDB), originated from ~280 US cancer clinics (~800 sites of care) between 01/2011-06/2023. The prevalence of ESR1mut, PIK3CAmut, AKT1, PTENmut, and PTEN copy loss were calculated in tissue (TBx) and liquid biopsies (LBx) collected at time of 1st, 2nd, and 3rd lines of therapy. The co-occurrence of GA in TBx was evaluated. Results: Among patients with a TBx collected around therapy initiation (n=2,536), 81.5% (2,066) was collected at 1 st , 10.2% (258) at 2 nd , and 8.3% (212) at 3 rd line. Among patients with a LBx collected around therapy initiation (n=545), 47% (256) was collected at 1 st , 33.2% (181) at 2 nd , and 19.8% (108) at 3 rd line. In TBx, the prevalence of GA detected in 1 st , 2 nd , and 3 rd lines were 58.6% (1,210), 67.4% (174), and 71.2% (151), respectively. In LBx, the prevalence was 42.7% (121), 65.7% (119), and 60.1% (65), respectively. Among LBx with tumor fraction ³1%, the prevalence was 67.9% (74/109), 89.1% (81/91), and 84.3% (43/51). Among patients with a GA detected in TBx 1 st (n=1,210), 2 nd (n=174), and 3 rd (n=151) lines, both ESR1mut and a PIK3 pathway GA was detected in 7.4% (90), 12.1% (21), and 23.8% (36), respectively. Conclusions: In our dataset, 42-59% of patients with HR(+) HER2(-) MBC have at least one GA detected by TBx or LBx in 1 st line, with prevalence increasing in later lines of therapy to 60-71% due to acquisition of an ESR1mut. PTEN copy loss is detected at much higher rates in TBx than LBx, consistent with the known inherent limitations of ctDNA testing. Serial genomic testing with LBx with reflex TBx if alterations are not identified should strongly be considered with the recent approvals of several molecularly targeted agents for HR(+) HER2(-) MBC. [Table: see text]
Pilot evaluation of allostatic load and breast cancer characteristics in a predominantly Han Chinese population.
Authors: Wenjing Gou, Qin Zou, Ruth C. Carlos
Journal: Journal of Clinical Oncology (2024)

e12570 Background: To determine the effects of allostatic load (AL), a measure of cumulative physiological effects of chronic stress due to adverse social determinants of health, on breast cancer (BC) characteristics in Chinese individuals. Methods: A pilot sample of185 women with newly diagnosed BC at Sichuan People’s hospital from 2018 to 2023 and complete AL data were included. AL used 10 markers (total cholesterol, low-density lipoprotein, albumin, glomerular filtration rate, white blood cell count, C-reactive protein, systolic and diastolic blood pressure, body mass index and heart rate). AL was assigned 1 point for each marker value in the worst quartile. The sum of the points represented the AL composite measure. Using linear and logistic regression, we determined the association of AL with age and educational attainment and with tumor ER+ and PR+ status. Results: Participants were 98.37% Han Chinese, mean age 51 (range 27-78). 23.24% attained college-level education or above. Higher AL trended to correlate with less than college-level educational attainment (coefficient=-0.60, p=0.058). In a univariable model, AL correlated with ER+ (OR=0.80, P=0.039) and PR+ (OR=0.81, P&lt;0.001) BC. Adjusting for age and educational attainment, AL trends remained positive but not significant with ER+ BC (OR =0.82, P=0.092). Conclusions: Similar to US patients, AL may represent a physiologic correlate of adverse social conditions and worse BC characteristics. Results remain to be confirmed in a larger population.