Citations

PURPOSE To investigate the clinical behavior of breast cancer in young BRCA carriers according to the specific BRCA gene ( BRCA1 v BRCA2 ) and the association of the timing of genetic testing (before v at diagnosis) with prognosis. METHODS This was an international, multicenter, hospital-based, retrospective cohort study that included 4,752 patients harboring germline pathogenic/likely pathogenic variants (PVs) in BRCA1 or BRCA2 , who were diagnosed with stage I-III invasive breast cancer at 40 years or younger between January 2000 and December 2020 in 78 centers worldwide (ClinicalTrials.gov identifier: NCT03673306 ). RESULTS Compared with BRCA2 carriers (n = 1,683), BRCA1 carriers (n = 3,069) had more frequently hormone receptor–negative (74.4% v 15.5%) and high-grade (77.5% v 49.1%) tumors. Similar outcomes were observed in BRCA1 and BRCA2 carriers but with a different pattern and risk of disease-free survival events over time. Compared with patients tested for BRCA at diagnosis (ie, between 2 months before and up to 6 months after diagnosis; n = 1,671), those tested before diagnosis (ie, any time up to 2 months before diagnosis; n = 411) had smaller tumors (T1: 61.3% v 32.4%), less nodal involvement (N0: 65.9% v 50.8%), less frequently received chemotherapy (84.4% v 92.9%), and axillary dissection (37.5% v 47.4%). Patients tested before diagnosis had better overall survival (OS; unadjusted hazard ratio [HR], 0.61 [95% CI, 0.40 to 0.92]); however, this result lost statistical significance after adjustment for potential confounders including tumor stage (adjusted HR, 0.74 [95% CI, 0.47 to 1.15]). CONCLUSION This global study provides evidence on the different clinical behavior of breast cancer in young BRCA1 and BRCA2 carriers. Identifying a BRCA PV in healthy individuals was associated with earlier-stage breast cancer diagnosis and lower treatment burden, as well as better unadjusted OS.

Objectives To evaluate the benefit of neoadjuvant chemotherapy (NAC) for patients with high‐risk upper tract urothelial carcinoma (UTUC) using a large, well‐curated multi‐institutional database. Patients and Methods This study was a multi‐institutional retrospective analysis conducted by the UTUC Collaborative Network (UCAN), combining data from 2276 patients with UTUC who underwent radical nephroureterectomy at seven high‐volume tertiary care centres in the United States. The UCAN data were analysed to evaluate the impact of response to NAC on survival outcomes in patients with UTUC. Results A total of 378 patients in the UCAN database underwent NAC. On final surgical pathology, 101 patients (26.8%) had ≤ypT1N0 disease and were defined as NAC treatment responders. Patients who responded to NAC had significantly longer overall survival (OS) and progression‐free survival (PFS) compared to non‐responders. At 5 years post‐surgery, 81.5% of responders were alive compared to 59.8% of non‐responders. The median OS and PFS times among non‐responders were 7.0 years (95% confidence interval [CI] 5.6–9.7) and 6.0 years (95% CI 4.6–9.3) respectively, while the median OS and PFS were not reached among responders. Limitations of this study include its retrospective design, heterogeneity in chemotherapy regimens, and the absence of clearly defined patient selection criteria for treatment. Conclusion These data suggest that NAC can play a pivotal role in the treatment of well‐selected UTUC patients who respond positively. Non‐responders had clearly inferior outcomes. More work is needed to find predictors of response which can improve patient selection.

Background Immune checkpoint inhibitors (ICIs) are recommended to treat patients with deficient mismatch repair/microsatellite instability high (dMMR/MSI-H) metastatic colorectal cancer (mCRC). Pivotal trials have fixed a maximum ICI duration of 2 years, without a compelling rationale. A shorter treatment duration has the potential to improve patients' quality of life and reduce both toxicity and cost without compromising efficacy. Here we examine whether early treatment discontinuation (ETD) before 13 months in patients without progressive disease (PD) can lead to similar long-term disease control compared with a longer treatment duration (LTD). Methods To assess whether ETD is associated with similar outcomes compared with LTD, we assembled an international cohort of patients with dMMR/MSI-H mCRC treated with ICIs who stopped treatment for a reason other than PD within 395 days (ETD group) and compared them to those who continued for >395 days (LTD group). Outcomes were adjusted for patient/tumor characteristics. Primary endpoint was progression-free survival (PFS) and secondary endpoints were objective response rate (ORR), overall survival (OS) and safety. Results Of 976 patients, 137 and 394 were allocated to the ETD and LTD groups, respectively. In the ETD group, treatment was discontinued due to toxicity (n=56), objective response (n=43), surgery (n=28), patient decision (n=2) or other reasons (n=8). Baseline characteristics were well balanced between the two groups: 22% in both groups received both anti-programmed death-(ligand) 1 (anti-PD-(L)1) + anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4); all others received anti-PD-(L)1 monotherapy. ORR to ICIs was 81% in both groups. Median duration of treatment was ~7 months in the ETD and ~24 months in the LTD group. After a median follow-up of 44 months (IQR: 30–67), similar PFS (HR: 0.92, 95% CI: 0.60 to 1.40, p=0.69) and OS (HR: 1.15, 95% CI: 0.66 to 1.99, p=0.62) from the start of ICIs were observed in ETD and LTD patients. In the ETD group, 28 (20%) patients had a PFS event and 9 restarted ICIs with a disease control rate of 66%. Conclusions In our international series of dMMR/MSI-H mCRC, ETD of ICIs in the absence of PD did not seem detrimental in terms of PFS and OS compared with continuing treatment beyond 1 year. Randomized clinical trials to compare short and long treatment duration are now warranted.

Abstract The immune system is a key player in the onset and progression of neurodegenerative disorders. While brain resident immune cell‐mediated neuroinflammation and peripheral immune cell (eg, T cell) infiltration into the brain have been shown to significantly contribute to Alzheimer's disease (AD) pathology, the nature and extent of immune responses in the brain in the context of AD and related dementias (ADRD) remain unclear. Furthermore, the roles of the peripheral immune system in driving ADRD pathology remain incompletely elucidated. In March of 2023, the Alzheimer's Association convened the Alzheimer's Association International Conference (AAIC), Advancements: Immunity, to discuss the roles of the immune system in ADRD. A wide range of topics were discussed, such as animal models that replicate human pathology, immune‐related biomarkers and clinical trials, and lessons from other fields describing immune responses in neurodegeneration. This manuscript presents highlights from the conference and outlines avenues for future research on the roles of immunity in neurodegenerative disorders. Highlights The immune system plays a central role in the pathogenesis of Alzheimer's disease. The immune system exerts numerous effects throughout the brain on amyloid‐beta, tau, and other pathways. The 2023 AAIC, Advancements: Immunity, encouraged discussions and collaborations on understanding the role of the immune system.

Abstract Background Immunoglobulin (Ig) measurements in the clinical laboratory have been traditionally performed by nephelometry, turbidimetry, electrophoresis, and ELISA assays. Mass spectrometry (MS) measurements have the potential to provide deeper insights on the nature of these markers. Content Different approaches—top-down, middle-down, or bottom-up—have been described for measuring specific Igs for endogenous monoclonal immunoglobulins (M-proteins) and exogenous therapeutic monoclonal antibody therapies (t-mAbs). Challenges arise in distinguishing the Ig of interest from the polyclonal Ig background. MS is emerging as a practical method to provide quantitative analysis and information about structural and clonal features that are not easily determined by current clinical laboratory methods. This review discusses clinically implemented examples, including isotyping and quantification of M-proteins and quantitation of t-mAbs within the polyclonal Ig background, as examples of how MS can enhance our detection and characterization of Igs. Summary This review of current clinically available MS proteomic tests for Igs highlights both analytical and nonanalytical challenges for implementation. Given the new insight into Igs from these methods, it is hoped that vendors, laboratorians, healthcare providers, and payment systems can work to overcome these challenges and advance the care of patients.

Background: The BeatAML Master Trial (BAMT) began in 2016 with a goal of determining the feasibility of a precision-medicine approach in treating acute myeloid leukemia (AML) in older adults ≥ 60 years of age where outcomes are poor. At the time, standard of care (SOC) for older patients with AML was intensive 7+3 chemotherapy (cytarabine + daunorubicin) if fit and hypomethylating agents (HMA: azacitidine or decitabine) if unfit. Besides confirming the feasibility, the early results (2019) from the Master Trial suggested that patients who received therapy on one of the sub-studies had a lower early death rate and superior overall survival compared to patients receiving off-protocol SOC, which was primarily single-agent HMA at the time. Since then, the 2019 approval of venetoclax (ven) + azacitidine for older unfit AML patients has been transformative and emerged as the SOC. Using data from the BAMT from 2016-2024, we suggest that knowing the comprehensive genomic profile of AML at the time of diagnosis is still beneficial in determining therapy that would lead to the optimal outcome and that development of targeted therapies and combination regimens with ven/HMA is still needed. Methods: This is a retrospective analysis of 1096 patients who consented and enrolled on the BAMT (NCT03013998) from Nov 2016 through Jun 2024. Patients ≥ 60 years with newly diagnosed AML were included. Patients underwent therapy on a BeatAML sub-study based on their genetics (N=433) or treatment off-protocol (N=663). We divided the patients according to what therapy they received: (1) Non-Intensive (Off-Protocol, N=121), (2) Ven/HMA (Off-Protocol, N=234), (3) Non-Intensive (Sub-Study, N=407), (4) Intensive (Sub-Study, N=26), and (5) Intensive (Off-Protocol, N=155). 94 patients received no treatment and 59 were unknown. Non-intensive therapies included primarily targeted agents or non-ven combinations. We analyzed baseline characteristics and demographics, overall survival (OS), and the impact of allogenic stem cell transplant (SCT). OS, using Kaplan-Meier method, was measured from the start of therapy to all-cause death, censoring patients at last follow-up. Results: Characteristics and demographics were similar between Groups 1, 2 and 3. Group 4 and 5 were treated with intensive chemotherapy and their characteristics are reflective of younger/fit patients appropriate for the intensive regimen. Groups 4 and 5 also had the longest median OS (mOS) of 40.2 months (95% CI: 13.9-not reached (NR)) and 42.3 months (95% CI: 25.1-NR) respectively. Group 3, which included patients treated with a non-intensive, targeted therapy on a sub-study, had an mOS of 14.0 months (95% CI: 12.3-16.7), which was similar to Group 2, treated with Ven/HMA, that had an mOS of 13.2 months (95% CI: 10.9-16.3). Lastly, patients in Group 1, who were treated primarily with HMA monotherapy, did poorly in comparison, with an mOS of 6.0 months (95% CI: 3.3-10.1). Additionally, we looked at the cumulative incidence rate (CIR) of SCT. The CIR in 12 months of Group 1 was 9.8% (95% CI: 6.9-13.4), Group 2: 5.4% (95% CI: 2.2-10.7), Group 3 and 4 combined: 35.0% (95% CI: 628.1-42.1), and Group 5: 13.1% (95% CI: 6.9-13.4). In a multi-variable analysis, after adjusting for typical favorable risk factors like NPM1 mutations and core binding factor, SCT was highly significant (p<0.0001) in improving OS with a hazard ratio of 0.23 (95% CI: 0.16-0.32), and Group 3 performed similarly to Group 2 (p=0.20). Conclusions: First, our results suggest that it is clinically relevant to correctly identify whether an intensive chemotherapy, targeted-therapy, or ven/HMA regimen is best suited for older AML patients, for which a precision-medicine trial is ideal for. Secondly, in this group of patients, our results show that patients treated with a non-intensive targeted therapy (Group 3) has a similar mOS to those treated with ven/HMA (Group 2). Especially after controlling for patient characteristics, patients in Group 2 performed similar to those in Group 3 (p=0.20). Patients in Group 3 were treated on Beat AML sub-studies which included targeted therapy alone or with non-venetoclax combinations, which is a strong rationale for continued development of targeted agents to optimize toxicity and quality of life with similar survival. Lastly, this data also supports the need to improve the ven/HMA SOC by developing combination regimens with targeted agents to further improve outcomes.

Background: Mutations of isocitrate dehydrogenase (IDH) are recurrent in acute myeloid leukemia (AML) and the prevalence increases with age. The prognostic impact of IDH1 and IDH2 mutations remains controversial. IDH inhibitors are small molecules that bind within the IDH enzymatic active site, blocking aberrant 2-hydroxyglutarate production and inducing myeloid differentiation. While they can lead to differentiation syndrome, they generally have a more favorable side-effect profile, making them an attractive option for older patients. We aimed to describe the prevalence and prognostic impact of IDH mutations in newly diagnosed (ND) AML patients ≥ 60 years in a large cohort of patients treated on a Leukemia and Lymphoma Society-sponsored trial. Methods: We performed a retrospective observational analysis including patients ≥ 60 years with ND AML who were enrolled on the Beat AML clinical trial (NCT03013998) before May 10, 2023. Patients were treated with a variety of treatment regimens. Cytogenetic analysis and next-generation sequencing (FoundationOne®Heme) were obtained. Mutations were considered present at any detectable VAF. Cox proportional hazard models were used to describe the relative risk of each variable on death over time from the date of trial inclusion. Results: A total of 1023 patients with ND AML were identified. Patients had a median age of 72 (range 60-92) years and the majority were non-Hispanic White (83.2%), and male (57.6%). Ninety-nine (9.7%) patients were IDH1MUT, 193 (18.9%) patients were IDH2MUT including 10 (1.0%) patients with a co-occurring IDH1 and IDH2 gene mutations. Both IDH1MUT and IDH2MUT were associated with 2022 ELN favorable-risk (26.3% and 22.3% for IDH1 and IDH2 respectively, vs 15.5% overall (P<0.001)). IDH1MUT significantly co-occurred with DNMT3AMUT (42.4%), NPM1MUT (44.4%) and less frequently with TP53MUT (10.1%) (P<0.001 for all). IDH2MUT was associated with DNMT3AMUT (35.8%), NPM1MUT (31.1%), SRSF2MUT (38.3%), and less frequently with TET2MUT (6.7%) and TP53MUT (9.3%) (P<0.001 for all). Normal karyotype was higher in IDH1MUT (P<0.001) and IDH2MUT (P<0.001), whereas complex karyotype (P<0.001 for both) and core-binding factor AML (P=0.047, P=0.015) were lower in IDH1MUT and IDH2MUT. To evaluate the impact of IDH mutations in patients ≥ 60 years, we focused on patients evaluable for outcome treated with lower-intensity therapy (LIT) (N=674), and intensive chemotherapy (IC) (N=178), separately. Among the LIT treated patients, 96 patients received treatment with an IDH inhibitor, and 237 patients received a hypomethylating agent (HMA) plus venetoclax. For patients treated with LIT, the hazard ratios (HRs) of death over time were 0.58 [95% CI 0.47-0.72; P<0.002], 0.81 [95% CI 0.59-1.13; P=0.214] and 0.56 [95% CI 0.44-0.72; P<0.001] for IDHMUT, IDH1MUT, IDH2MUT respectively. Among patients receiving IC, the HRs were 1.05 [95% CI 0.68-1.69; P=0.777], 0.70 [95% CI 0.31-1.61; P=0.406] and 1.27 [95% CI 0.77-2.1; P=0.352] for IDHMUT, IDH1MUT, and IDH2MUT respectively. The HR of death for IDH1MUT patients treated with LIT with the addition of an IDH1 inhibitor (N=24) was significantly lower (HR 0.47 [95% CI 0.24-0.92; P=0.027] vs IDH1MUT patients treated without an IDH1 inhibitor, while an IDH2 inhibitor did not change survivial outcomes in patients with IDH2MUT (N=71). Discussion: To our knowledge this is the largest retrospective study characterizing the prevalence of IDH mutations in patients ≥ 60 years with AML. We demonstrated that IDH mutations were detected in ~27% of older patients with AML. Although there could have been selection bias as the Beat AML study had separate IDHMUT study arms, these findings are concordant with other studies showing an increase in frequency of IDH mutations with age. IDH2MUT was associated with a lower HR of death among patients treated with LIT, which was not seen in patients receiving IC. The high prevalence of IDH mutations suggests that IDH inhibitors used as single agents or in combination with lower-intensity therapies are an important class of drugs for this older patient population as they are generally well tolerated, that need further investigation.

Background While central nervous system (CNS) disease is found in minority of patients (pts) at diagnosis of Ph+ ALL, later relapses can occur in pts despite adequate CNS prophylaxis. CNS disease can be managed with varying combinations of systemic, radiation, and intrathecal (IT) therapy and can be associated with significant toxicity, especially in older pts. While there are more durable systemic responses with 2nd or 3rd generation tyrosine kinase inhibitors (TKIs) based combinations, CNS penetration can vary by TKI. In this large multi-center study, we analyze the incidence of CNS disease in Ph+ ALL in the context of induction therapies and survival post relapse. Methods We conducted a multicenter observational study in collaboration with 10 U.S. academic centers under the COMMAND consortium and reviewed the incidence of CNS relapse in 505 Ph+ ALL pts. We evaluated baseline characteristics, treatment given prior to CNS relapse, and outcome post relapse. Results Baseline characteristics, initial treatment and outcome prior to CNS relapse Eighteen (3.56%) pts were identified to have CNS disease at relapse. Median age of the pts in years (yrs) was 51 (range [R], 22-75), median white blood cell (WBC) was 33.3 x 10(9)/L (R, 2.1-200) and 6 (33%) pts had additional cytogenetic abnormalities at diagnosis. Sixty-one percent (n= 11) of pts received intensive chemotherapy (IC) during induction; 2 (11%), 14 (78%) and 2(11%) of pts received 1st, 2nd or 3rd generation TKI-based combination during induction, respectively. All of pts achieved complete remission (CR), 45.5% achieved complete molecular remission (CMR) at 3 months from the time of diagnosis. Five (28%) pts received allogeneic stem cell transplantation (allo-HCT) as a consolidation therapy. Treatment received at CNS relapse and response The median time to CNS relapse after induction was 10.8 months (mo) (R, 2-79). All pts except 1 had isolated CNS relapse after CR1, 4/18 (22%) pts had T315I mutation at relapse. Twelve (67%) and 6 (33%) pts received intrathecal chemotherapy (IT) with TKI and systemic chemotherapy + TKI in addition to IT, respectively. Eleven (61%) pts received dasatinib, 5 (28%) pts received ponatinib and one (6%) pts each received bosutinib and imatinib at relapse. Ninety-three percent of pts achieved CR (n=3, not evaluable). Six (33%) pts underwent allo-HCT after CNS relapse, one of these transplanted pts had second allo-HCT. Survival after CNS relapse The median relapse free survival (RFS) and overall survival (OS) after CNS relapse was 9.8 (95% CI: 3.80-15.76) and 13.87 (95% CI: 4.08-23.65) mo, respectively. In subset analysis, we compared survival outcome among pts who had relapse without CNS involvement (n= 160/505 [32%]). The median RFS (9.9 vs 9.8, p= 0.88) and OS (31.53 vs 28.80, p= 0.57) after relapse was not significantly different among pts who had relapse with or without CNS involvement, respectively. We also compared OS among pts without relapse to those with relapse. The median OS was not reached (NR; 73% alive at 5 years), 28.80 and 31.53 months (p= <0.001) among pts with no relapse, relapse with CNS and without CNS involvement, respectively. Conclusion Our retrospective analysis from a large database showed that CNS relapses were uncommon (3.56%) in adult pts with Ph+ ALL. A majority of pts (89%) received a 2nd or a 3rd generation TKI during induction. Approximately one quarter of pts with CNS relapse had emergence of T315I mutation. While almost all pts achieved CR, the RFS was relatively short. We did not see significant differences in survival among pts who had relapse with or without CNS involvement.