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Objective: To characterize associations between carbohydrate antigen 19–9 (CA19–9) dynamics during neoadjuvant therapy (NT) and survival for patients with pancreatic ductal adenocarcinoma (PDAC). Background: Although normalization of CA19–9 during NT is associated with improved outcomes following PDAC resection, we hypothesize that CA19–9 dynamics during NT can improve prognostication. Methods: Characteristics for patients with PDAC undergoing NT (July 2011–October 2018) with ≥3 CA19–9 results (bilirubin<2mg/dL) were collected and grouped by CA19–9 dynamics. Nonproducers (<1 U/ml) were excluded, and normal was ≤35 U/ml. Postresection survival was compared among groups. Results: Of 431 patients, 166 had eligible CA19–9 values. Median baseline CA19–9 was 98 U/ml. Overall 2-year postresection recurrence-free survival (RFS) and overall survival (OS) were 37% and 63%, respectively. Patients with normalization (53%) had improved 2-year RFS (47% vs. 28%, P = 0.01) and OS (75% vs. 49%, P = 0.01). CA19–9 dynamics during NT were analyzed by shape, direction, and normalization creating response types ("A-B-C-D-E"). Type A was "Always" decreasing to normalization, B "Bidirectional" with eventual normalization, C "Consistently" normal, D any "Decrease" without normalization, and E "Elevating" without normalization. Types A and B responses were associated with the longest postresection 2-year RFS (51% and 56%) and OS (75% and 92%, respectively) whereas Types D and E had the worst outcomes. After adjusting for node-positivity, perineural invasion, and margin-positivity, CA19–9 response types were independently associated with both RFS and OS, and predicted outcomes are better than CA19–9 normalization alone (likelihood ratio test RFS P < 0.001, OS P = 0.01). Conclusions: This novel A-B-C-D-E classification of CA19–9 dynamics during NT was associated with postresection outcomes more precisely than CA19–9 normalization alone. [ABSTRACT FROM AUTHOR]

Background: Genetic evaluation and testing for hereditary breast and ovarian cancer (HBOC) remain suboptimal. The authors evaluated the feasibility of using a screening tool at a breast imaging center to increase HBOC assessment referrals. Methods: A brief questionnaire based on the National Comprehensive Cancer Network HBOC genetic counseling referral guidelines was developed and added to the standard intake forms of patients undergoing mammography at a community breast imaging center from 2012 through 2015. Patients who met the criteria in the guidelines were referred for genetic counseling. Results: A total of 34,851 patients were screened during the study period, and 1246 (4%) patients were found to be eligible for referral; 245 of these patients made a genetic counseling appointment, and 142 patients received genetic counseling. Forty patients (28%) had a personal history of breast cancer but were not previously tested. Following counseling, 105 patients were tested for BRCA1/2. Eight patients (8%) tested positive for a pathogenic mutation and nine (9%) had a variant of unknown significance. Although they tested negative, many patients met the criteria to add breast magnetic resonance imaging to their screening due to greater than 20% lifetime breast cancer risk based on their family cancer history. This study led to improved clinical risk management in 67% of the patients who underwent genetic counseling. Conclusions: This study shows that large‐scale screening of patients for HBOC syndromes at time of breast imaging is practical and highly feasible. The screening tool identified women with actionable BRCA1/2 mutations and mutation‐negative but high‐risk women, leading to significant changes in their risk management; these women would otherwise have been missed. Lay Summary: Hereditary breast and ovarian cancer (HBOC) caused by pathogenic mutations in breast cancer genes (BRCA1/BRCA2) increase an individual's lifetime risk of getting HBOC.Identifying these high‐risk individuals and using proven preventive clinical risk management strategies can significantly reduce their lifetime risk of HBOC.Using an innovative family cancer history questionnaire, 34,000 women were screened at a community breast imaging center, and genetic counseling and testing were provided to eligible women from the screening.Several women at high risk for HBOC were identified and this led to positive clinical risk management changes.These women would have been missed if not for intervention. This study establishes a new methodology to screen women for hereditary breast and ovarian cancer (HBOC). Through genetic counseling and BRCA gene testing, this study identifies women at risk for HBOC and potentiates changes in their clinical risk management. [ABSTRACT FROM AUTHOR]

Purpose: To determine the efficacy and safety of risk-adapted combinations of androgen signaling inhibitors and inform disease classifiers for metastatic castration-resistant prostate cancers., Patients and Methods: In a modular, randomized phase II trial, 192 men were treated with 8 weeks of abiraterone acetate, prednisone, and apalutamide (AAPA; module 1) and then allocated to modules 2 or 3 based on satisfactory (≥50% PSA decline from baseline and <5 circulating tumor cell/7.5 mL) versus unsatisfactory status. Men in the former were randomly assigned to continue AAPA alone (module 2A) or with ipilimumab (module 2B). Men in the latter group had carboplatin + cabazitaxel added to AAPA (module 3). Optional baseline biopsies were subjected to correlative studies., Results: Median overall survival (from allocation) was 46.4 [95% confidence interval (CI), 39.2-68.2], 41.4 (95% CI, 33.3-49.9), and 18.7 (95% CI, 14.3-26.3) months in modules 2A (n = 64), 2B (n = 64), and 3 (n = 59), respectively. Toxicities were within expectations. Of 192 eligible patients, 154 (80.2%) underwent pretreatment metastatic biopsies. The aggressive-variant prostate cancer molecular profile (defects in ≥2 of p53, RB1, and PTEN) was associated with unsatisfactory status. Exploratory analyses suggested that secreted phosphoprotein 1-positive and insulin-like growth factor-binding protein 2-positive macrophages, druggable myeloid cell markers, and germline pathogenic mutations were enriched in the unsatisfactory group., Conclusions: Adding ipilimumab to AAPA did not improve outcomes in men with androgen-responsive metastatic castration-resistant prostate cancer. Despite the addition of carboplatin + cabazitaxel, men in the unsatisfactory group had shortened survivals. Adaptive designs can enrich for biologically and clinically relevant disease subgroups to contribute to the development of marker-informed, risk-adapted therapy strategies in men with prostate cancer., (©2024 American Association for Cancer Research.)

The safety and efficacy of combining the isocitrate dehydrogenase-1 (IDH1) inhibitor ivosidenib (IVO) with the BCL2 inhibitor venetoclax (VEN; IVO + VEN) ± azacitidine (AZA; IVO + VEN + AZA) were evaluated in four cohorts of patients with IDH1-mutated myeloid malignancies (n = 31). Most (91%) adverse events were grade 1 or 2. The maximal tolerated dose was not reached. Composite complete remission with IVO + VEN + AZA versus IVO + VEN was 90% versus 83%. Among measurable residual disease (MRD)-evaluable patients (N = 16), 63% attained MRD--negative remissions; IDH1 mutation clearance occurred in 64% of patients receiving ≥5 treatment cycles (N = 14). Median event-free survival and overall survival were 36 [94% CI, 23-not reached (NR)] and 42 (95% CI, 42-NR) months. Patients with signaling gene mutations appeared to particularly benefit from the triplet regimen. Longitudinal single-cell proteogenomic analyses linked cooccurring mutations, antiapoptotic protein expression, and cell maturation to therapeutic sensitivity of IDH1-mutated clones. No IDH isoform switching or second-site IDH1 mutations were observed, indicating combination therapy may overcome established resistance pathways to single-agent IVO., Significance: IVO + VEN + AZA is safe and active in patients with IDH1-mutated myeloid malignancies. Combination therapy appears to overcome resistance mechanisms observed with single-agent IDH-inhibitor use, with high MRD-negative remission rates. Single-cell DNA ± protein and time-of-flight mass-cytometry analysis revealed complex resistance mechanisms at relapse, highlighting key pathways for future therapeutic intervention. This article is highlighted in the In This Issue feature, p. 247., (©2023 American Association for Cancer Research.)

Background: A von Hippel Lindau (VHL) mutation or functional inactivation occurs in the a large proportion of patients with clear-cell renal cell carcinoma (ccRCC), which results in the dysregulation of a number of key cellular functions. A high throughput screen and candidate compound assessment revealed that agents with proteasome inhibition properties were able to stabilize point-mutated VHL and restore some of its functions., Patients and Methods: Nine patients with histologically confirmed metastatic ccRCC with disease progression during at least 1 previous systemic therapy were treated with carfilzomib at a dose of 20 mg/m 2 over 30 minutes via intravenous (I.V.) infusion on days 1 and 2 and a dose of 56 mg/m 2 over 30 minutes via I.V. infusion on days 8, 9, 15, and 16 of each 4-week cycle., Results: The study was stopped after 9 patients were enrolled because of futility. Of the 9 patients treated in the study, all patients had disease progression within 4 months, with a median time of 1.8 months (95% confidence interval, 0.8-3.6 months). No patient showed a response according to Response Evaluation Criteria In Solid Tumors. Three patients showed a best response of stable disease. The most common side effects were musculoskeletal pain, elevated creatinine level, anemia, hyperkalemia, leukopenia, lymphopenia, and fatigue., Conclusion: Although the negative safety and efficacy results of this study do not favor the use of carfilzomib for the treatment of ccRCC, previous studies have shown selected patients achieved partial or complete response to this class of agent. Further preclinical investigations to evaluate the molecular characteristics of the patients who respond to proteasome inhibitors will better characterize the underlying mechanism of response, and might allow for the selection of an appropriate patient population in future studies., (Copyright © 2019 Elsevier Inc. All rights reserved.)