tbuckley/cabot-search huggingface dataset:
Early tumor response in first‐line palbociclib plus AI in Chinese women with HR+/HER2- advanced breast cancer: Primary analysis of a multicenter, prospective real-world study.
Authors: Wen-Ming Cao, Xiaolin Li, Zhengyang Xu, Haiqi Lu, Zhanhong Chen, Junqing Chen, Xiaojia Wang, Hai Hu, Weiwu Ye, Rong Wang
Journal: Journal of Clinical Oncology (2024)

e13078 Background: The CDK4/6 inhibitors (CDK4/6i) and aromatase inhibitors (AIs) regimen is the first-line standard for HR+/HER2- advanced breast cancer. Despite this, high-risk patients often receive combination chemotherapy for quicker disease control, a practice supported by anecdotal evidence of the efficacy of the CDK4/6i and AI combination but lacking rigorous research validation. Early tumor shrinkage (ETS), a prognostic marker in colorectal cancer, remains undefined in HR+ breast cancer. This study (NCT04858997) aims to investigate the early effectiveness of the CDK4/6i and AI combination through ETS, addressing a significant gap in the literature. Methods: This study enrolled HR+/HER2- advanced breast cancer patients diagnosed between April 2021 and October 2023, who were treatment-naïve for their advanced disease and consented to palbociclib and AI therapy. Participants underwent CT scans to evaluate treatment response at baseline, week 4, week 12, and every 12 weeks thereafter. The study primarily investigated ETS, defined herein as a ≥10% reduction in the sum of diameters of target lesions by week 4. Secondary endpoints encompassed TTR, ORR, and PFS. Results: The study enrolled 30 patients with a median age of 55 years (range 29-76); 30% were premenopausal, and 40% presented with ≥3 metastatic sites. Visceral metastases were observed in 53.3% of the cohort (N=16). ETS was achieved in 73.3% of patients at the first assessment 4 weeks post-treatment initiation, with 68.8% in patients with visceral metastases and 78.8% in those without. The mTTR=3 months, differing between patients with visceral metastases (6 months) and those without (3 months). The overall response rate (ORR) was 63.3%. The ETS outcomes predict the best response in patients, with 77.3% reaching ETS eventually achieving partial or complete response (PR/CR), compared to only 25% of those not reaching ETS. Conclusions: This study validates the CDK4/6i and AI combination's early effectiveness in HR+/HER2- advanced breast cancer, showing that 4-week treatment responses predict best of response outcomes. Achieving ETS is closely linked to a higher likelihood of therapeutic success, underscoring its value as a prognostic marker for informed therapy choices.
Genomic and tumor microenvironment dynamics of brain metastases in breast cancer.
Authors: Dharmini Manogna, Sharon Wu, Sachin Kumar Deshmukh, Joanne Xiu, Sima Ehsani, Ragisha Gopalakrishnan, Ana Cristina Sandoval-Leon, Sarah L Sammons, George W. Sledge, Stephanie L. Graff
Journal: Journal of Clinical Oncology (2024)

1018 Background: Brain metastases (BM) in breast cancer (BC) have a poor prognosis, with median survival at 7.2-13 months. Interplay between genomic evolution of cancer cells and development of BM is obscure. We sought to identify genomic aberrations associated with BM. Methods: We included 14095 BC samples: 429 BM, 7858 extra-cerebral metastases (ECM) and 5808 primary tumors (PT) were analyzed by next generation sequencing of DNA (NextSeq, 592 genes and NovaSeq, WES) and RNA (NovaSeq, WTS) (Caris Life Sciences, AZ). Tumor mutational burden-high (TMB-H) was defined as ≥10 mt/MB. Cut-off for PD-L1 immunohistochemistry positivity was ≥2 intensity and &gt;5% staining (SP142). Global loss of heterozygosity (gLOH) used a cut-off of ≥ 16%. PAM50 was evaluable for a subset (n=9724, 69%) with WTS data. Statistical significance determined using chi-square and Mann-Whitney U test and adjusted for multiple comparisons (q&lt;0.05). Results: Median age was lower in BM than ECM and PT (55 vs 62 vs 59 years, q&lt;0.05). BM subtype was triple negative (TNBC, 40.1%), HR+/HER2- (30.5%), or HER2+ (29.4%) vs. ECM primarily HR+/HER2- (65.4%) and PT HER2+ (52.5%). BM were Basal-like (35.3%) or HER2-enriched (35.3%), whereas ECM were Luminal B (47.2%) and PT were Basal-like (34.4%) or Luminal B (34.6%). The Table summarizes molecular findings. In HR+/HER2- BC, BM were associated with TMB-H vs. ECM and PT (q&lt;0.05). BM had higher GATA3-mt and ESR1-mt compared to PT (q&lt;0.05). In HER2+ BC, BM had lower PD-L1+ (11.8% vs 39.3%) and higher ESR1-mt than PT. BM had higher ERBB2-amp (93.5% vs 75.2%) and RARA-amp (27.3% vs 6.7%) than PT (q&lt;0.05). TNBC BM had higher proportion of TMB-H tumors but lower PD-L1+ (20.8% vs 50.7%) than PT. BM had increased gLOH than ECM (59.2% vs 36.2%). PIK3CA was lower in BM vs. ECM. In all subtypes, BM, when compared to ECM and PT respectively, were associated with decreased AR+ (HR+/HER2-: 57.7% vs 80.8% vs 85.7%; HER2+: 54.4% vs 77.1% vs 81%; TNBC: 15.1% vs 27.7% vs 23.1%), increased dendritic cell infiltration (HR+/HER2-: 3.2% vs 2.6% vs 2.5%; HER2+: 3.85% vs 2.41% vs 2.36%; TNBC: 3.96% vs 2.89% vs 3.05%) but lower IFN score (HR+/HER2-: -0.56 vs -0.41 vs-0.35; HER2+: -0.53 vs -0.39 vs -0.30; TNBC: -0.55 vs -0.30 vs -0.28). Conclusions: BM in BC are more frequently associated with TNBC and Basal-like BC phenotypes than ECM or PTs. BM have a higher proportion of ESR1-mut than PTs, highlighting a possible association between endocrine resistance and development of BM. BM had lower IFN score and PDL-1 expression highlighting an immunosuppressed tumor microenvironment. [Table: see text]
Natural History of Nonmetastatic Prostate Cancer Managed With Watchful Waiting
Authors: Eugenio Ventimiglia, Rolf Gedeborg, Johan Styrke, David Robinson, Pär Stattin, Hans Garmo
Journal: JAMA Network Open (2024)

Importance It is uncertain to what extent watchful waiting (WW) in men with nonmetastatic prostate cancer (PCa) and a life expectancy of less than 10 years is associated with adverse consequences. Objective To report transitions to androgen deprivation therapy (ADT), castration-resistant prostate cancer (CRPC), death from PCa, or death from other causes in men treated with a WW strategy. Design, Setting, and Participants This nationwide, population-based cohort study included men with nonmetastatic PCa diagnosed since 2007 and registered in the National Prostate Cancer Register of Sweden with WW as the primary treatment strategy and with life expectancy less than 10 years. Life expectancy was calculated based on age, the Charlson Comorbidity Index (CCI), and a drug comorbidity index. Observed state transition models complemented observed data to extend follow-up to more than 20 years. Analyses were performed between 2022 and 2023. Exposure Nonmetastatic PCa. Main Outcomes and Measures Transitions to ADT, CRPC, death from PCa, and death from other causes were measured using state transition modeling. Results The sample included 5234 men (median [IQR] age at diagnosis, 81 [79-84] years). After 5 years, 954 men with low-risk PCa (66.2%) and 740 with high-risk PCa (36.1%) were still alive and not receiving ADT. At 10 years, the corresponding proportions were 25.5% (n = 367) and 10.4% (n = 213), respectively. After 10 years, 59 men with low-risk PCa (4.1%) and 221 with high-risk PCa (10.8%) had transitioned to CRPC. Ten years after diagnosis, 1330 deaths in the low-risk group (92.3%) and 1724 in the high-risk group (84.1%) were from causes other than PCa. Conclusions and Relevance These findings suggest that the WW management strategy is appropriate for minimizing adverse consequences of PCa in men with a baseline life expectancy of less than 10 years.
Pretreatment neutrophil to lymphocyte ratio as a predictor of pathological complete response to neoadjuvant immunotherapy in early breast cancer.
Authors: Tian Du, Yan Wang, Zixuan Zhao, Yuhong Chen, Rong Deng, Jun Tang
Journal: Journal of Clinical Oncology (2024)

e12545 Background: Neoadjuvant immunotherapy has been increasingly used in early breast cancer, while lack of accessible predictive biomarkers of response remains an open question. High pretreatment neutrophil to lymphocyte ratio (NLR) was associated with worse prognosis and treatment responses to neoadjuvant chemotherapy in multiple cancers including breast cancer. However, it remains unclear whether NLR was associated with response to neoadjuvant immunotherapy in early breast cancer. Methods: We retrospectively analyzed 89 early breast cancer patients who received neoadjuvant chemotherapy in combination with at least 4 cycles of immunotherapy and subsequent breast surgery in Sun Yat-sen University Cancer Center. Pretreatment NLR was calculated, and Miller-Payne grade 5 in primary tumor site was considered pathological complete response (pCR) to neoadjuvant therapy. Univariate and multivariate analyses were used to evaluate the associations between clinicopathological markers and pCR. Results: 49.4% (44/89) of the patients achieved pCR. Compared to non-pCR patients, pCR patients had significantly lower pretreatment NLR (1.93 vs 2.87, p&lt;0.001) and lower percentage of pretreatment cT3/T4 stage (11.4% vs 37.7%, p=0.006), and received more cycles of neoadjuvant immunotherapy (6.5 vs 6.0, p&lt;0.05). More pCR patients received TCb based neoadjuvant therapy (86.4% vs 51.1%, p&lt;0.001). In multivariate analysis, the pretreatment NLR (p=0.002) and cT3/T4 (p=0.010, as compared to cT1/T2) were independent predictive factors for pCR. Conclusions: Lower pretreatment NLR was associated with higher possibility of achieving pCR in early breast cancer treated with neoadjuvant immunotherapy. [Table: see text]
Deliberate inclusion of multiple co-correlated gene target sets during discovery for improved biomarker translation to a clinical assay in early-stage breast cancer.
Authors: Elizabeth Cormier-May, Michael Colbus, Martin J Keiser
Journal: Journal of Clinical Oncology (2024)

e12560 Background: Co-correlation between gene targets provides a more robust, and often nonlinear, understanding of human biology, resulting in more accurate and reliable diagnostics. When translating from discovery to a clinical assay, detectability of promising targets often hinders diagnostic development. Translating a single set of co-correlated targets becomes more challenging, as the success of the program is dependent on the interrelationship between all targets and the ability of the entire set to translate clinically. Given target translation uncertainty, we hypothesized that the deliberate inclusion of multiple independent sets of co-correlated targets during discovery could bridge the gap between promising biology and a clinically viable assay. We set out to discover and clinically validate multiple sets of co-correlated targets required for noninvasive breast cancer detection. Methods: Nonlinear statistical methods were repeatedly applied to microarray gene expression profiles from peripheral blood (PBMCs) obtained from 140 patients with and without breast cancer. Four independent cohorts were used for subsequent studies to assess efficacy and reproducibility of discovered targets. In total, five independent sets of highly efficacious co-correlated targets, totaling 26 unique genes, were discovered and analytically validated across the five patient cohorts (n=357). A sixth independent cohort of 197 plasma samples (breast cancer n=116, controls n=81) was obtained and used to clinically translate and validate the 26 targets using real-time qPCR (qPCR). Results: qPCR revealed strong and reproducible clinical signal from 8/26 previously discovered targets (Table). To evaluate the efficacy of the targets, an 8-gene signature was trained on the PBMC discovery cohort, achieving &gt;99% sensitivity, 83% specificity, indicating a promising classifier could be trained from the 8 qPCR targets. During CLIA validation of the assay, in normalized qPCR data from 87 patients, the 8-gene assay achieved a statistically significant &gt;99% sensitivity, 89% specificity in stage I breast cancer. Conclusions: Given the performance observed from the 8-gene qPCR assay, we conclude that the deliberate inclusion of multiple sets of co-correlated targets, including those considered mathematically redundant during discovery, contributed to the success of a clinically viable assay for the detection of early-stage breast cancer in plasma. [Table: see text]
Efficacy of subsequent treatments after disease progression on CDK4/6 inhibitors therapy in patients with hormone receptor-positive metastatic breast cancer: A Kaplan-Meier derived individual-patient data meta-analysis.
Authors: Lis Victoria Ravani, Pedro Calomeni, Maysa Vilbert, Thiago Madeira, Ming Wang, Daxuan Deng, Laura Testa, Katherine Clifton, Seth Andrew Wander, Maryam B. Lustberg
Journal: Journal of Clinical Oncology (2024)

1065 Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy (ET) are standard-of-care for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/ HER2-) metastatic breast cancer (mBC). Yet, disease progression is common in these patients. In the absence of established guidelines for optimal sequencing post-progression, we conducted a pooled analysis of patient data to assess the efficacy of subsequent treatment options following disease progression on CDK4/6i therapy. Methods: We conducted a systematic review and meta-analysis, searching PubMed, Embase, Cochrane, and conference proceedings for randomized controlled trials (RCTs) and observational cohort studies reporting subsequent treatment post-CDK4/6i progression in patients with HR+HER2-mBC from 2016 to December 2023. We performed a pooled analysis of Kaplan-Meier-derived individual patient data for progression-free survival (PFS) and overall survival (OS). Subgroups analysis according to drug type, and a sensitivity analysis including only RCTs were also conducted. Statistical analysis was performed with R Statistical Software. Results: Of 12,895 identified records, 18 studies (7 RCTs and 11 cohort studies) comprising 4,868 patients with HR+HER2-mBC were included. Maintaining treatment with a CDK4/6i post-CDK4/6i progression was associated with longer PFS (HR: 0.64; 95% CI: 0.54-0.76; p&lt;0.01; n=1,397) and prolonged OS (HR: 0.70; 95% CI: 0.61-0.79; p&lt;0.01; n=2,369) compared with ET monotherapy. The PFS benefit was seen in both continuing the prior CDK4/6i (HR 0.62; 95%CI: 0.54-0.72; p&lt;0.01; n=1,178) or switching to a different CDK4/6i (HR 0.49; 95%CI: 0.30-0.82; p&lt;0.01; n=638). Subsequent therapy with PI3K/AKT/mTOR inhibitors plus ET also achieved longer PFS (HR: 0.74; 95% CI: 0.61-0.90; p&lt;0.01; n=744), but significantly shorter OS (HR 1.36; 95%CI: 1.09-1.71; p&lt;0.01; n=1,564) compared with ET monotherapy. PFS with chemotherapy was not different from ET monotherapy (HR 0.93; 95%CI: 0.76-1.13; p=0.45; n=879) but exhibited shorter OS (HR 1.55; 95%CI: 1.38-1.72; p &lt; 0.01; n=2,476). Sensitivity analyses including only RCTs, confirmed the greater PFS of maintaining CDK4/6i plus ET compared with ET monotherapy (HR: 0.69 95% CI: 0.57-0.83; p&lt;0.01; n=751). Conclusions: This extensive data pool of RCTs and cohort studies suggests the potential clinical benefit of continued CDK4/6i after disease progression compared to ET monotherapy. Data from phase III trials will further aid in understanding this question. Our data also supports current guideline recommendations of ET-based therapies over chemotherapy as the preferred treatment sequencing in HR+ HER2- mBC.
Switching from nonsteroidal aromatase inhibitors to exemestane and its impact on menopausal symptoms.
Authors: Julia Blanter, Charlotte Ezratty, Anahi McIntyre, Tianxiang Sheng, Amy Tiersten
Journal: Journal of Clinical Oncology (2024)

e13098 Background: Aromatase inhibitors (AIs) are the most used adjuvant treatment in post-menopausal women with favorable oncotype, hormone receptor-positive (HR+) early breast cancer. Nonsteroidal AIs, such as anastrozole and letrozole, are associated with menopausal side effects including arthralgias, vaginal dryness, and hot flashes. Steroidal AIs, such as exemestane, however, have mild androgenic activity, thus minimizing the risk for these side effects. While studies show exemestane exhibits less bone toxicity compared to anastrozole, there has not yet been a proven significant difference in all menopausal symptoms. Nevertheless, switching from nonsteroidal to steroidal AI is still commonly seen in clinical practice. In this study, we aimed to examine the impact of switching from nonsteroidal to steroidal AI on menopausal side effects. Methods: We performed a retrospective review of patients diagnosed with HR+ breast cancer managed at an urban academic center from 2010-2023. Patients initially treated with anastrozole or letrozole and switched to exemestane were identified. Pathology records, treatment plans, and documented side effects were abstracted from medical records, as were baseline demographics. Symptoms were graded based on severity before and after each hormone therapy: mild grade described intermittent symptoms that did not require intervention; moderate grade described persistent daily symptoms or those that improved with additional intervention; severe grade described persistent disabling symptoms that required change in hormone therapy. Wilcoxon signed-rank tests were used to compare severity of menopausal symptoms before and after switching to exemestane. Results: There were 128 patients included in the study. Median age at diagnosis was 62.5 years; 13% pre-menopausal, 80% post-menopausal, 4% perimenopausal, and 3% unknown. Most patients were diagnosed with invasive ductal carcinoma (80%) and 45% were found to have stage IA breast cancer. The median amount of time on first and second lines of endocrine therapy were 11 and 25 months, respectively. Ninety-six patients (75%) reported menopausal symptoms on nonsteroidal AI, and 66% subsequently switched to exemestane due to severity of these symptoms. The most reported symptoms were arthralgias (79%), hot flashes (27%), body aches (25%), fatigue (10%), and vaginal dryness (9%). Of those with menopausal symptoms, 51% noted a decrease in symptom severity after switching to exemestane: 4 improved from moderate to mild, 21 from severe to moderate, and 24 from severe to mild. This decrease in severity was statistically significant across all menopausal symptoms (p&lt;0.001). Conclusions: HR+ breast cancer patients exhibited a significant decrease in all menopausal symptoms when switching from nonsteroidal to steroidal AI. Further research is needed to examine the impact of this switch on a wider range of symptoms.
Access to Prostate-Specific Antigen Testing and Mortality Among Men With Prostate Cancer
Authors: Hari S. Iyer, Benjamin V. Stone, Charlotte Roscoe, Mei-Chin Hsieh, Antoinette M. Stroup, Charles L. Wiggins, Fredrick R. Schumacher, Scarlett L. Gomez, Timothy R. Rebbeck, Quoc-Dien Trinh
Journal: JAMA Network Open (2024)

Prostate-specific antigen (PSA) screening for prostate cancer is controversial but may be associated with benefit for certain high-risk groups.
HER2 low hormone positive breast cancer: Unveiling the driver.
Authors: Alaa Eltelbany, Heba Elsheredy, Rasha Elsaka, Saied A. Elnowiem, Waleed O. Arafat
Journal: Journal of Clinical Oncology (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=&lt;0.001. ER2-low were more likely to be ductal carcinoma (88.1% vs. 80.4%; p=0.004), and to have Ki67 level &lt;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.