Association between tumor-infiltrating lymphocytes and survival in patients with metastatic breast cancer receiving first-line chemotherapy: analysis of CALGB 40502.

Association of stromal tumor-infiltrating lymphocytes (sTILs) with survival outcomes among patients with metastatic breast cancer (MBC) remains unclear. The primary objective was to evaluate the association of sTILs with progression-free survival in randomized phase III trial CALGB 40502. sTILs were associated with progression-free and overall survival in chemotherapy-treated MBC when controlling for treatment arm; however, this effect did not remain significant after additional adjustment for hormone receptor status. CALGB is now part of the Alliance for Clinical Trials in Oncology. Trial Registration: ClinicalTrials.gov: NCT00785291.

Radiation therapy and IRreversible electroporation for intermediate risk prostate cancer (RTIRE).

INTRODUCTION: Radiation Therapy and IRreversible Electroporation for Intermediate Risk Prostate Cancer (RTIRE) is a phase II clinical trial testing combination of radiation therapy and irreversible electroporation for intermediate risk prostate cancer BACKGROUND: PCa is the most common non-cutaneous cancer in men and the second leading cause of cancer death in men. PCa treatment is associated with long term side effects including urinary, sexual, and bowel dysfunction. Management of PCa is based on risk stratification to prevent its overtreatment and associated treatment-related toxicity. There is increasing interest in novel treatment strategies, such as focal therapy, to minimize treatment associated morbidity. Focal therapy alone has yet to be included in mainstream guidelines, given ongoing concerns with potentially higher risk of recurrence. We hypothesize combining focal therapy with whole gland, reduced dose radiotherapy will provide acceptable oncologic efficacy with minimal treatment associated morbidity. RTIRE is a phase II single institution, investigator-initiated study combining a local ablative technique though local irreversible electroporation (IRE) with MR guided RT (MRgRT) to treat the entire prostate. The goal is to provide excellent oncologic outcomes and minimize treatment related side effects through leveraging benefits of locally ablative therapy with established radiation treatment techniques. METHODS: A total of 42 men with intermediate risk PCa per NCCN guidelines and focal grade group (GG) 2 or 3, Gleason Score (GS) 3 + 4 or GS 4 + 3, cancer in an MRI target will be enrolled. Patients with MRI visible foci of GG2/GG3 will undergo focal therapy with IRE of this lesion. Following successful focal therapy, patients will then undergo a course of reduced dose, whole gland MRgRT with either 32.5 Gy in 5 Fractions or 22 Gy in 2 fractions. The primary objective of the study is to determine safety. Secondary outcomes include evaluation of oncologic efficacy (as measured by the proportion of patients free of clinically significant cancer as defined as > Grade Group 1 at 1-year follow-up biopsy), imaging characteristics of patients pre and post RTIRE, impact on quality of life (QoL), and PSA kinetics. DISCUSSION: Combining IRE with a reduced dose radiotherapy may offer a new treatment paradigm for PCa by both reducing treatment effects of full dose radiotherapy and minimizing the risk of recurrence observed with focal therapy. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05345444. Date of registration: April 25, 2022. PROTOCOL VERSION: 6.0, July 7, 2023.

Aspirin vs Placebo as Adjuvant Therapy for Breast Cancer: The Alliance A011502 Randomized Trial.

Importance: Observational studies of survivors of breast cancer and prospective trials of aspirin for cardiovascular disease suggest improved breast cancer survival among aspirin users, but prospective studies of aspirin to prevent breast cancer recurrence are lacking. Objective: To determine whether aspirin decreases the risk of invasive cancer events among survivors of breast cancer. Design, Setting, and Participants: A011502, a phase 3, randomized, placebo-controlled, double-blind trial conducted in the United States and Canada with 3020 participants who had high-risk nonmetastatic breast cancer, enrolled participants from 534 sites from January 6, 2017, through December 4, 2020, with follow-up to March 4, 2023. Interventions: Participants were randomized (stratified for hormone receptor status [positive vs negative], body mass index [≤30 vs >30], stage II vs III, and time since diagnosis [<18 vs ≥18 months]) to receive 300 mg of aspirin (n = 1510) or placebo once daily (n = 1510) for 5 years. Main Outcomes and Measures: The primary outcome was invasive disease-free survival. Overall survival was a key secondary outcome. Results: A total of 3020 participants were randomized when the data and safety monitoring committee recommended suspending the study at the first interim analysis because the hazard ratio had crossed the prespecified futility bound. By median follow-up of 33.8 months (range, 0.1-72.6 months), 253 invasive disease-free survival events were observed (141 in the aspirin group and 112 in the placebo group), yielding a hazard ratio of 1.27 (95% CI, 0.99-1.63; P = .06). All invasive disease-free survival events, including death, invasive progression (both distant and locoregional), and new primary events, were numerically higher in the aspirin group, although the differences were not statistically significant. There was no difference in overall survival (hazard ratio, 1.19; 95% CI, 0.82-1.72). Rates of grades 3 and 4 adverse events were similar in both groups. Conclusion and Relevance: Among participants with high-risk nonmetastatic breast cancer, daily aspirin therapy did not improve risk of breast cancer recurrence or survival in early follow-up. Despite its promise and wide availability, aspirin should not be recommended as an adjuvant breast cancer treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT02927249.

A Single Arm Phase 2 Trial of Trametinib in Patients With Locally Advanced or Metastatic Epithelioid Hemangioendothelioma.

PURPOSE: Epithelioid hemangioendothelioma (EHE) is a rare vascular cancer with pathogenic TAZ-CAMTA1 operating as an oncogenic driver through activation of MAPK pathway. Trametinib is an inhibitor of MEK, a critical kinase in the MAPK pathway. We sought to evaluate the effect of trametinib in patients with EHE. PATIENTS AND METHODS: A phase 2 trial of trametinib was conducted in patients with locally advanced or metastatic EHE. Eligibility requirements included evidence of tumor progression or presence of EHE-related pain requiring opiates for management prior to enrollment. The primary endpoint was objective response rate (ORR) per RECIST1.1 in cases with TAZ-CAMTA1 confirmed by fusion-FISH. Secondary objectives were to estimate ORR for all patients, median PFS, 2-year OS rate, patient safety, and change in patient-reported global health and pain scores per PROMIS questionnaires. RESULTS: 44 patients enrolled and 42 started trametinib. TAZ-CAMTA1 was detected in 27 tumor samples. The ORR was 3.7% (95% CI: 0.094, 19.0), median PFS was 10.4 months (95% CI: 7.1, NA), and 2-year OS rate was 33.3% (95% CI: 19.1, 58.2) in the target population. Median pain intensity and interference scores improved significantly after 4 weeks of trametinib in patients using opiates. Common AEs related to trametinib were rash, fatigue, nausea/vomiting, diarrhea/constipation, alopecia and edema; one Grade 5 ARDS/pneumonitis was related to trametinib. CONCLUSIONS: Trametinib was associated with reduction in EHE-related pain and median PFS of more than 6 months providing palliative benefit in patients with advanced EHE, but the trial did not meet the ORR goal.

Prostate-Specific Membrane Antigen-Targeting Alpha Emitter via Antibody Delivery for Metastatic Castration-Resistant Prostate Cancer: A Phase I Dose-Escalation Study of 225Ac-J591.

PURPOSE: Novel therapies are needed to extend survival in metastatic castration-resistant prostate cancer (mCRPC). Prostate-specific membrane antigen (PSMA), a cell surface antigen overexpressed in PC, provides a validated target. This dose-escalation study investigated the safety, efficacy, maximum tolerated dose (MTD), and recommended phase II dose (RP2D) for 225Ac-J591, anti-PSMA monoclonal antibody J591 radiolabeled with the alpha emitter actinium-225. METHODS: Following investigational new drug-enabling preclinical studies, we enrolled patients with progressive mCRPC that was refractory to or who refused standard treatment options (including androgen receptor pathway inhibitor and had received or been deemed ineligible for taxane chemotherapy). No selection for PSMA was performed. Patients received a single dose of 225Ac-J591 at one of seven dose-escalation levels followed by expansion at the highest dose. Primary end point of dose-escalation cohort was determination of dose-limiting toxicity (DLT) and RP2D. RESULTS: Radiochemistry and animal studies were favorable. Thirty-two patients received 225Ac-J591 in an accelerated dose-escalation design (22 in dose escalation, 10 in expansion). One patient (1 of 22; 4.5%) experienced DLT in cohort 6 (80 KBq/kg) but none in cohort 7; MTD was not reached, and RP2D was the highest dose level (93.3 KBq/kg). The majority of high-grade adverse events (AEs) were hematologic with an apparent relationship with administered radioactivity. Nonhematologic AEs were generally of low grade. Prostate-specific antigen (PSA) declines and circulating tumor cell (CTC) control were observed: 46.9% had at least 50% PSA decline at any time (34.4% confirmed PSA response), and protocol-defined CTC count response occurred in 13 of 22 (59.1%). CONCLUSION: To our knowledge, this is the first-in-human phase I dose-escalation trial of a single dose of 225Ac-J591 in 32 patients with pretreated progressive mCRPC demonstrated safety and preliminary efficacy signals. Further investigation is underway.

Data-driven optimization of version 9 American Joint Committee on Cancer staging system for anal cancer.

INTRODUCTION: The American Joint Committee on Cancer (AJCC) staging system undergoes periodic revisions to maintain contemporary survival outcomes related to stage. Recently, the AJCC has developed a novel, systematic approach incorporating survival data to refine stage groupings. The objective of this study was to demonstrate data-driven optimization of the version 9 AJCC staging system for anal cancer assessed through a defined validation approach. METHODS: The National Cancer Database was queried for patients diagnosed with anal cancer in 2012 through 2017. Kaplan-Meier methods analyzed 5-year survival by individual clinical T category, N category, M category, and overall stage. Cox proportional hazards models validated overall survival of the revised TNM stage groupings. RESULTS: Overall, 24,328 cases of anal cancer were included. Evaluation of the 8th edition AJCC stage groups demonstrated a lack of hierarchical prognostic order. Survival at 5 years for stage I was 84.4%, 77.4% for stage IIA, and 63.7% for stage IIB; however, stage IIIA disease demonstrated a 73.0% survival, followed by 58.4% for stage IIIB, 59.9% for stage IIIC, and 22.5% for stage IV (p <.001). Thus, stage IIB was redefined as T1-2N1M0, whereas Stage IIIA was redefined as T3N0-1M0. Reevaluation of 5-year survival based on data-informed stage groupings now demonstrates hierarchical prognostic order and validated via Cox proportional hazards models. CONCLUSION: The 8th edition AJCC survival data demonstrated a lack of hierarchical prognostic order and informed revised stage groupings in the version 9 AJCC staging system for anal cancer. Thus, a validated data-driven optimization approach can be implemented for staging revisions across all disease sites moving forward.

Immunological and clinicopathological features predict HER2-positive breast cancer prognosis in the neoadjuvant NeoALTTO and CALGB 40601 randomized trials.

The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease.

Age, Body Mass Index, Tumor Subtype, and Racial and Ethnic Disparities in Breast Cancer Survival.

Importance: Black women in the United States have higher breast cancer (BC) mortality rates than White women. The combined role of multiple factors, including body mass index (BMI), age, and tumor subtype, remains unclear. Objective: To assess the association of race and ethnicity with survival among clinical trial participants with early-stage BC (eBC) according to tumor subtype, age, and BMI. Design, Setting, and Participants: This cohort study analyzed survival data, as of November 12, 2021, from participants enrolled between 1997 and 2010 in 4 randomized adjuvant chemotherapy trials: Cancer and Leukemia Group B (CALGB) 9741, 49907, and 40101 as well as North Central Cancer Treatment Group (NCCTG) N9831, legacy groups of the Alliance of Clinical Trials in Oncology. Median follow-up was 9.8 years. Exposures: Non-Hispanic Black and Hispanic participants were compared with non-Hispanic White participants within subgroups of subtype (hormone receptor positive [HR+]/ERBB2 [formerly HER2] negative [ERBB2-], ERBB2+, and HR-/ERBB2-), age (<50, 50 to <65, and ≥65 years), and BMI (<18.5, 18.5 to <25.0, 25.0 to <30.0, and ≥30.0). Main Outcomes and Measures: Recurrence-free survival (RFS) and overall survival (OS). Results: Of 9479 participants, 436 (4.4%) were Hispanic, 871 (8.8%) non-Hispanic Black, and 7889 (79.5%) non-Hispanic White. The median (range) age was 52 (19.0-89.7) years. Among participants with HR+/ERBB2- tumors, non-Hispanic Black individuals had worse RFS (hazard ratio [HR], 1.49; 95% CI, 1.04-2.12; 5-year RFS, 88.5% vs 93.2%) than non-Hispanic White individuals, although the global test for association of race and ethnicity with RFS was not significant within any tumor subtype. There were no OS differences by race and ethnicity in any subtype. Race and ethnicity were associated with OS in young participants (age <50 years; global P = .008); young non-Hispanic Black participants (HR, 1.34; 95% CI, 1.04-1.71; 5-year OS, 86.6% vs 92.0%) and Hispanic participants (HR, 1.62; 95% CI, 1.16-2.29; 5-year OS, 86.2% vs 92.0%) had worse OS than young non-Hispanic White participants. Race and ethnicity were associated with RFS in participants with BMIs of 25 to less than 30, with non-Hispanic Black participants having worse RFS (HR, 1.81; 95% CI, 1.23-2.68; 5-year RFS, 83.2% vs 87.3%) than non-Hispanic White participants. Conclusions and Relevance: In this cohort study, racial and ethnic survival disparities were identified in patients with eBC receiving standardized initial care, and potentially at-risk subgroups, for whom focused interventions may improve outcomes, were found.

Hyper-Dependence on NHEJ Enables Synergy between DNA-PK Inhibitors and Low-Dose Doxorubicin in Leiomyosarcoma.

PURPOSE: Leiomyosarcoma (LMS) is an aggressive sarcoma for which standard chemotherapies achieve response rates under 30%. There are no effective targeted therapies against LMS. Most LMS are characterized by chromosomal instability (CIN), resulting in part from TP53 and RB1 co-inactivation and DNA damage repair defects. We sought to identify therapeutic targets that could exacerbate intrinsic CIN and DNA damage in LMS, inducing lethal genotoxicity. EXPERIMENTAL DESIGN: We performed clinical targeted sequencing in 287 LMS and genome-wide loss-of-function screens in 3 patient-derived LMS cell lines, to identify LMS-specific dependencies. We validated candidate targets by biochemical and cell-response assays in vitro and in seven mouse models. RESULTS: Clinical targeted sequencing revealed a high burden of somatic copy-number alterations (median fraction of the genome altered =0.62) and demonstrated homologous recombination deficiency signatures in 35% of LMS. Genome-wide short hairpin RNA screens demonstrated PRKDC (DNA-PKcs) and RPA2 essentiality, consistent with compensatory nonhomologous end joining (NHEJ) hyper-dependence. DNA-PK inhibitor combinations with unconventionally low-dose doxorubicin had synergistic activity in LMS in vitro models. Combination therapy with peposertib and low-dose doxorubicin (standard or liposomal formulations) inhibited growth of 5 of 7 LMS mouse models without toxicity. CONCLUSIONS: Combinations of DNA-PK inhibitors with unconventionally low, sensitizing, doxorubicin dosing showed synergistic effects in LMS in vitro and in vivo models, without discernable toxicity. These findings underscore the relevance of DNA damage repair alterations in LMS pathogenesis and identify dependence on NHEJ as a clinically actionable vulnerability in LMS.

Effect of Sepsis on Death as Modified by Solid Organ Transplantation.

Background: Patients who have undergone solid organ transplants (SOT) have an increased risk for sepsis compared with the general population. Paradoxically, studies suggest that SOT patients with sepsis may experience better outcomes compared with those without a SOT. However, these analyses used previous definitions of sepsis. It remains unknown whether the more recent definitions of sepsis and modern analytic approaches demonstrate a similar relationship. Methods: Using the Weill Cornell-Critical Care Database for Advanced Research, we analyzed granular physiologic, microbiologic, comorbidity, and therapeutic data in patients with and without SOT admitted to intensive care units (ICUs). We used a survival analysis with a targeted minimum loss-based estimation, adjusting for within-group (SOT and non-SOT) potential confounders to ascertain whether the effect of sepsis, defined by sepsis-3, on 28-day mortality was modified by SOT status. We performed additional analyses on restricted populations. Results: We analyzed 28 431 patients: 439 with SOT and sepsis, 281 with SOT without sepsis, 6793 with sepsis and without SOT, and 20 918 with neither. The most common SOT types were kidney (475) and liver (163). Despite a higher severity of illness in both sepsis groups, the adjusted sepsis-attributable effect on 28-day mortality for non-SOT patients was 4.1% (95% confidence interval [CI], 3.8-4.5) and -14.4% (95% CI, -16.8 to -12) for SOT patients. The adjusted SOT effect modification was -18.5% (95% CI, -21.2 to -15.9). The adjusted sepsis-attributable effect for immunocompromised controls was -3.5% (95% CI, -4.5 to -2.6). Conclusions: Across a large database of patients admitted to ICUs, the sepsis-associated 28-day mortality effect was significantly lower in SOT patients compared with controls.

Local Recurrence After Breast-Conserving Therapy in Patients With Multiple Ipsilateral Breast Cancer: Results From ACOSOG Z11102 (Alliance).

PURPOSE: Breast-conserving therapy (BCT) is the preferred treatment for unifocal breast cancer (BC). The oncologic safety of BCT for multiple ipsilateral breast cancer (MIBC) has not been demonstrated in a prospective study. ACOSOG Z11102 (Alliance) is a phase II, single-arm, prospective trial designed to evaluate oncologic outcomes in patients undergoing BCT for MIBC. PATIENTS AND METHODS: Women age 40 years and older with two to three foci of biopsy-proven cN0-1 BC were eligible. Patients underwent lumpectomies with negative margins followed by whole breast radiation with boost to all lumpectomy beds. The primary end point was cumulative incidence of local recurrence (LR) at 5 years with an a priori rate of clinical acceptability of <8%. RESULTS: Among 270 women enrolled between November 2012 and August 2016, there were 204 eligible patients who underwent protocol-directed BCT. The median age was 61 years (range, 40-87 years). At a median follow-up of 66.4 months (range, 1.3-90.6 months), six patients developed LR for an estimated 5-year cumulative incidence of LR of 3.1% (95% CI, 1.3 to 6.4). Patient age, number of sites of preoperative biopsy-proven BC, estrogen receptor status and human epidermal growth factor receptor 2 status, and pathologic T and N categories were not associated with LR risk. Exploratory analysis showed that the 5-year LR rate in patients without preoperative magnetic resonance imaging (MRI; n = 15) was 22.6% compared with 1.7% in patients with a preoperative MRI (n = 189; P = .002). CONCLUSION: The Z11102 clinical trial demonstrates that breast-conserving surgery with adjuvant radiation that includes lumpectomy site boosts yields an acceptably low 5-year LR rate for MIBC. This evidence supports BCT as a reasonable surgical option for women with two to three ipsilateral foci, particularly among patients with disease evaluated with preoperative breast MRI.

Outcome of Patients With Malignant Peripheral Nerve Sheath Tumors Enrolled on Sarcoma Alliance for Research Through Collaboration (SARC) Phase II Trials.

BACKGROUND: Evaluation of prior phase II trials for malignant peripheral nerve sheath tumors (MPNST) may help develop more suitable trial endpoints in future studies. METHODS: We analyzed outcomes of patients with recurrent or unresectable/metastatic MPNST enrolled on prior Sarcoma Alliance for Research through Collaboration (SARC) phase II trials and estimated the progression-free survival (PFS). PFS from SARC006 (NCT00304083), the phase II trial of upfront chemotherapy in chemotherapy naïve patients, was analyzed separately. Impact of baseline enrollment characteristics on PFS was evaluated. RESULTS: Sixty-four patients (29 male, 35 female, median age 39 years (range 15-81)) with MPNST were enrolled on 1 of 5 trials of single agent or combination therapy that were determined to be inactive. Patients had received a median of 1 (range 0-5) prior systemic therapy, and most had undergone prior surgery (77%) and radiation (61%). Seventy-three percent had metastatic disease at enrollment. Median PFS was 1.77 months (95% CI, 1.61-3.45), and the PFS rate at 4 months was 15%. Greater number of prior systemic therapies and worse performance status were associated with inferior PFS. There was no significant difference in PFS based on age at enrollment, treatment trial, response criteria, presence of metastatic disease, disease site at enrollment, and prior surgery or radiation. In comparison, on the SARC006 trial the PFS rate at 4 months was 94% in 40 patients. CONCLUSION: These data provide a historical baseline PFS that may be used as a comparator in future clinical trials for patients with MPNST.

Bolus versus Continuous Intravenous Delivery of Doxorubicin in Soft-Tissue Sarcomas: Post Hoc Analysis of a Prospective Randomized Trial (SARC021/TH CR-406).

PURPOSE: Continuous intravenous infusion (CIV) of doxorubicin (DOX) versus bolus (BOL) may minimize dose-dependent DOX cardiomyopathy, but it is unclear whether this advantage is evident as employed in typical soft-tissue sarcoma (STS) treatment. The impact of administration mode on adverse events (AE) and efficacy were compared using data from a randomized trial of DOX-based therapy (SARC021/TH CR-406). EXPERIMENTAL DESIGN: In this post hoc analysis, CIV versus BOL was at discretion of the treating physician. Likelihood of AEs, and objective responses were assessed by adjusted logistic regression. Progression-free (PFS) and overall survival (OS) were compared using Kaplan-Meier, log-rank test, and adjusted Cox regression. RESULTS: DOX was administered by BOL to 556 and by CIV to 84 patients. Proportions experiencing hematologic, non-hematologic, or cardiac AEs did not differ by administration mode. Hematologic AEs were associated with age, performance status, and cumulative DOX. Non-hematologic AEs were associated with age, performance status, and cumulative evofosfamide. Cardiac AEs were only associated with cumulative DOX; there was no interaction between DOX dose and delivery mode. PFS and OS were similar (median PFS 6.14 months BOL vs. 6.11 months CIV, P = 0.47; median OS 18.4 months BOL vs. 21.4 months CIV, P = 0.62). PFS, OS, and objective responses were not associated with delivery mode. CONCLUSIONS: CIV was not associated with superior outcomes over BOL within DOX dosing limits of SARC021. Cardiac AEs were associated with increasing cumulative DOX dose. While not randomized with respect to DOX delivery mode, the results indicate that continued investigation of AE mitigation strategies is warranted.

Prognostic and Predictive Value of Immune-Related Gene Expression Signatures vs Tumor-Infiltrating Lymphocytes in Early-Stage ERBB2/HER2-Positive Breast Cancer: A Correlative Analysis of the CALGB 40601 and PAMELA Trials.

Importance: Both tumor-infiltrating lymphocytes (TILs) assessment and immune-related gene expression signatures by RNA profiling predict higher pathologic complete response (pCR) and improved event-free survival (EFS) in patients with early-stage ERBB2/HER2-positive breast cancer. However, whether these 2 measures of immune activation provide similar or additive prognostic value is not known. Objective: To examine the prognostic ability of TILs and immune-related gene expression signatures, alone and in combination, to predict pCR and EFS in patients with early-stage ERBB2/HER2-positive breast cancer treated in 2 clinical trials. Design, Setting, and Participants: In this prognostic study, a correlative analysis was performed on the Cancer and Leukemia Group B (CALGB) 40601 trial and the PAMELA trial. In the CALGB 40601 trial, 305 patients were randomly assigned to weekly paclitaxel with trastuzumab, lapatinib, or both for 16 weeks. The primary end point was pCR, with a secondary end point of EFS. In the PAMELA trial, 151 patients received neoadjuvant treatment with trastuzumab and lapatinib for 18 weeks. The primary end point was the ability of the HER2-enriched subtype to predict pCR. The studies were conducted from October 2013 to November 2015 (PAMELA) and from December 2008 to February 2012 (CALGB 40601). Data analyses were performed from June 1, 2020, to January 1, 2022. Main Outcomes and Measures: Immune-related gene expression profiling by RNA sequencing and TILs were assessed on 230 CALGB 40601 trial pretreatment tumors and 138 PAMELA trial pretreatment tumors. The association of these biomarkers with pCR (CALGB 40601 and PAMELA) and EFS (CALGB 40601) was studied by logistic regression and Cox analyses. Results: The median age of the patients was 50 years (IQR, 42-50 years), and 305 (100%) were women. Of 202 immune signatures tested, 166 (82.2%) were significantly correlated with TILs. In both trials combined, TILs were significantly associated with pCR (odds ratio, 1.01; 95% CI, 1.01-1.02; P = .02). In addition to TILs, 36 immune signatures were significantly associated with higher pCR rates. Seven of these signatures outperformed TILs for predicting pCR, 6 of which were B-cell related. In a multivariable Cox model adjusted for clinicopathologic factors, including PAM50 intrinsic tumor subtype, the immunoglobulin G signature, but not TILs, was independently associated with EFS (immunoglobulin G signature-adjusted hazard ratio, 0.63; 95% CI, 0.42-0.93; P = .02; TIL-adjusted hazard ratio, 1.00; 95% CI, 0.98-1.02; P = .99). Conclusions and Relevance: Results of this study suggest that multiple B-cell-related signatures were more strongly associated with pCR and EFS than TILs, which largely represent T cells. When both TILs and gene expression are available, the prognostic value of immune-related signatures appears to be superior.

Association of circulating markers with cognitive decline after radiation therapy for brain metastasis.

BACKGROUND: A recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline. METHODS: In this retrospective analysis of prospectively collected samples from a completed randomized clinical trial, patients provided blood samples every 3 months that were tested by genotyping and enzyme-linked immunosorbent assay, and results were analyzed in association with cognitive impairment. RESULTS: The APOE genotype was not associated with neurocognitive impairment at 3 months. However, low serum levels of ApoJ, ApoE, or ApoA protein (all P < .01) and higher amyloid beta (Aß 1-42) levels (P = .048) at baseline indicated a greater likelihood of neurocognitive decline at 3 months after SRS, whereas lower ApoJ levels were associated with decline after WBRT (P = .014). CONCLUSIONS: Patients with these pretreatment serum markers should be counseled about radiation-related neurocognitive decline.

Association of Long-term Outcomes With Stereotactic Radiosurgery vs Whole-Brain Radiotherapy for Resected Brain Metastasis: A Secondary Analysis of The N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group) Randomized Clinical Trial.

Importance: Long-term outcomes of radiotherapy are important in understanding the risks and benefits of therapies for patients with brain metastases. Objective: To determine how the use of postoperative whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) is associated with quality of life (QOL), cognitive function, and intracranial tumor control in long-term survivors with 1 to 4 brain metastases. Design, Setting, and Participants: This secondary analysis of a randomized phase 3 clinical trial included 48 institutions in the US and Canada. Adult patients with 1 resected brain metastases but limited to those with 1 to 4 brain metastasis were eligible. Unresected metastases were treated with SRS. Long-term survivors were defined as evaluable patients who lived longer than 1 year from randomization. Patients were recruited between July 2011 and December 2015, and data were first analyzed in February 2017. For the present study, intracranial tumor control, cognitive deterioration, QOL, and cognitive outcomes were measured in evaluable patients who were alive at 12 months from randomization and reanalyzed in June 2017. Interventions: Stereotactic radiosurgery or WBRT. Main Outcomes and Measures: Intracranial tumor control, toxic effects, cognitive deterioration, and QOL. Results: Fifty-four patients (27 SRS arm, 27 WBRT arm; female to male ratio, 65% vs 35%) were included for analysis with a median follow-up of 23.8 months. Cognitive deterioration was less frequent with SRS (37%-60%) compared with WBRT (75%-91%) at all time points. More patients declined by 2 or more standard deviations (SDs) in 1 or more cognitive tests for WBRT compared with SRS at 3, 6, and 9 months (70% vs 22%, 46% vs 19%, and 50% vs 20%, respectively). A 2 SD decline in at least 2 cognitive tests was associated with worse 12-month QOL in emotional well-being, functional well-being, general, additional concerns, and total scores. Overall QOL and functional independence favored SRS alone for categorical change at all time points. Total intracranial control for SRS alone vs WBRT at 12 months was 40.7% vs 81.5% (difference, -40.7; 95% CI, -68.1% to -13.4%), respectively. Data were first analyzed in February 2017. Conclusions and Relevance: The use of SRS alone compared with WBRT resulted in less cognitive deterioration among long-term survivors. The association of late cognitive deterioration with WBRT was clinically meaningful. A significant decline in cognition (2 SD) was associated with overall QOL. However, intracranial tumor control was improved with WBRT. This study provides detailed insight into cognitive function over time in this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT01372774; ALLIANCE/CCTG: N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group).

A FOXO1-dependent transcription network is a targetable vulnerability of mantle cell lymphomas.

Targeting lineage-defined transcriptional dependencies has emerged as an effective therapeutic strategy in cancer treatment. Through screening for molecular vulnerabilities of mantle cell lymphoma (MCL), we identified a set of transcription factors (TFs) including FOXO1, EBF1, PAX5, and IRF4 that are essential for MCL propagation. Integrated chromatin immunoprecipitation and sequencing (ChIP-Seq) with transcriptional network reconstruction analysis revealed FOXO1 as a master regulator that acts upstream in the regulatory TF hierarchy. FOXO1 is both necessary and sufficient to drive MCL lineage commitment through supporting the lineage-specific transcription programs. We further show that FOXO1, but not its close paralog FOXO3, can reprogram myeloid leukemia cells and induce B-lineage gene expression. Finally, we demonstrate that cpd10, a small molecule identified from an enriched FOXO1 inhibitor library, induces a robust cytotoxic response in MCL cells in vitro and suppresses MCL progression in vivo. Our findings establish FOXO1 inhibition as a therapeutic strategy targeting lineage-driven transcriptional addiction in MCL.