Citations

Abstract Background: Breast cancer (BC) in males represents a rare clinical entity, accounting about 1% of all breast malignancies diagnosed every year. Emerging evidence suggest that a gender medicine approach is critical in the research and treatment of cancer, based on the possibility that sex hormones, molecular differences, immune system, and other factors might play a crucial role in disease management. Here, we characterized molecular and immune differences between male BC (MaBC) and female BC (FeBC) across BC subtypes. Methods: 10,728 BC samples (male, n=137; female, n=10591) were analysed by next-generation sequencing (592, NextSeq; WES, NovaSeq), Whole Transcriptome Sequencing (WTS; NovaSeq) (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) totaled somatic mutations per tumor (high ≥10 mt/MB). Microsatellite-instability (MSI) was tested by IHC and NGS. Immune cell fractions were calculated by deconvolution of WTS: Quantiseq. Real world treatment-associated survival was extracted from insurance claims and calculated from sample collection to last contact using Kaplan-Meier estimates. Statistical significance was determined using chi-square and Mann-Whitney U test with p-values adjusted for multiple comparisons (q < 0.05). Results: MaBC represented higher HR+/HER2+ (6.61% vs 4.76%), HR+/HER2- (80.17% vs 60.66%) and lower HR-/HER2+ (1.65% vs 3.5%), TNBC (11.57% vs 31.08%) molecular subtypes compared to FeBC. Compared to HR+/HER2+ FeBC, MaBC had higher frequency of CHEK2, RAD51B, TSC1 mutation (Table 1) and RARα (100% vs 13.61%), DAXX (10% vs 0.16%) copy number alteration (all p < 0.05). HR+/HER2- MaBC had higher frequency of BRCA2, FOXA1, CREBBP, FLCN mutation (Table 1), and FGF3 (21.62% vs 14.31%), MRE11 (1.75% vs 0.23%), MEN1 (1.75% vs 0.13%) copy number alteration, but lower frequency of TP53, CHD1, ESR1 and AKT1 mutation (Table 1) (all p < 0.05). HR-/HER2+ MaBC had higher frequency of BRCA1 (p < 0.05) mutation (Table 1). Male TNBC had higher frequency of CDKN2A, KMT2D, STK11, ASXL1, MYC, NF2, PPM1D, WT1, EPHA2, AMER1, ARHGAP35 mutation (Table 1) and BCL6 (4.35% vs 0.05%) copy number alteration, but lower frequency of TP53 mutation (all p < 0.05) (Table 1). MaBC had higher AR protein expression (82.5% vs 60%) but lower frequency of fusion variant-AR (0.7% vs 3.9%) (all p < 0.05) compared to FeBC. There was no difference in TMB high (7.1% vs 8.4%, p = 0.5) and dMMR/MSI-H (1.8% vs 0.8%, p = 0.1). Analysis of inferred immune cell infiltrates showed that MaBC had increased immune cell infiltration of B cells (5.8% vs 5.3%) and M2 Mφ (4.9% vs 4.3%), but decreased infiltration of DC (2% vs 2.6%) (all p < 0.05). MaBC had increased expression of MHC class II gene HLA-DQB2 (FC: 1.3), but decreased expression of immune-related genes CD274 (FC: 1.2), IDO (FC: 1.4), IL1A (FC: 1.3) and IL12A (FC: 1.5) (all p < 0.05). Correlative analyses with survival will be presented at the meeting. Conclusions: These data indicate that MaBC has a differential mutational frequency, copy number alteration, immune gene expression and immune cell infiltration and overall survival compared to their FeBC counterparts. A better understanding of these sex-based differences with additional research may help inform disease outcomes, provide a rationale for tailored therapeutic approaches and design future treatments. Table 1. Mutation frequency in male and female breast cancer Citation Format: Dario Trapani, Sachin Deshmukh, Sharon Wu, Joanne Xiu, Phil Walker, Pooja Advani, Nancy Lin, Giuseppe Curigliano, Stephanie Graff, Chadi Nabhan, George Sledge Jr, Sara Tolaney, Jose Leone. Molecular and immunological landscape of sex-based differences in breast cancer: a distinct disease in men [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS13-09.

Abstract BACKGROUND: Anti-HER2 therapies have transformed the trajectory for patients with HER2-positive (HER2+) MBC. A subset of patients with HER2+ MBC do exceptionally well and remain on maintenance anti-HER2 therapy for many years. However, current therapy is non-curative and patients are treated indefinitely. While these therapies often are well-tolerated, they may cause significant toxicities, are expensive, and typically require frequent infusion and provider visits. Case reports and retrospective series demonstrate that some patients may do well after stopping anti-HER2 treatment. We currently lack prospective data on the likelihood of clinical impact of successful treatment discontinuation, outcomes among patients who progress and restart HER2-directed therapy, and tools to predict who may safely stop therapy. In this study, we will enroll pts with an exceptional response to anti-HER2 therapy. Pts may elect to either continue or stop anti-HER2 therapy and will be followed clinically and radiographically on a protocol-specified schedule. Considering the central role of patients in choosing the study intervention arm, and the unique nature of stopping therapy as a treatment intervention, patient advocates have been deeply involved in the study design to ensure patient concerns are being heard and addressed. We will retrospectively assess minimal residual disease (MRD), measured in plasma, as a biomarker of ongoing response, in a step toward shifting the treatment paradigm for pts with HER2+ MBC. METHODS: STOP-HER2 is a prospective, non-randomized, phase II, multicenter study of either continuation (cohort 1) or cessation (cohort 2) of anti-HER2 therapy in exceptional responders with HER2+ MBC. Eligible patients must have biopsy-proven HER2+ MBC by ASCO/CAP guidelines and must have been receiving first-line anti-HER2 therapy for MBC for at least 3 years without evidence of progressive disease (PD) as determined by the treating investigator. Patients with prior brain-only PD or oligo-PD outside the brain are eligible at least 2 years after local treatment to the central nervous system (CNS) and in absence of subsequent PD. Up to fifty-two participants will be enrolled into cohort 2, and an additional thirty participants enrolled into the cohort 1, at 10 US sites within the Translational Breast Cancer Research Consortium. Co-primary endpoints are the 1-year progression-free survival (PFS) in cohorts 2 and 1, separately. Secondary endpoints include the clinical benefit rate upon re-initiation of anti-HER2 therapy for patients in cohort 2 experiencing PD after treatment discontinuation; and 3-year overall survival in both cohorts. Correlative endpoints include MRD status at baseline and the correlation between MRD dynamics and outcomes. Patient-reported outcomes will be collected and analyzed, including quality of life, illness intrusiveness, financial toxicity, anxiety, and decision regret. The study will use a two-stage design to assess the primary objective of estimating the rate of participants who are free of progression at one year after discontinuing anti-HER2 therapy. If 50% or less are free of progression at one year, stopping HER2 therapy would not be considered a viable treatment plan (null hypothesis). The study is designed to have 80% power to reject the null hypothesis at the 10% type I error rate when 68% of exceptional responders are free of progression at one year after stopping HER2 therapy. STOP-HER2 began enrollment in Q2 2023 (NCT05721248). Citation Format: Heather Parsons, Kathryn Ruddy, Stefania Morganti, Karen Smith, Victoria Attaya, Eliza Kallfelz, Michelle DeMeo, Jamie LaScala, Shirley Mertz, Teri Pollastro, Patricia Spears, Adam Brufsky, Chau Dang, Susan Dent, Ahmed Elkhanany, WIlliam Gwin, Ciara O'Sullivan, Kathy Miller, Sara Nunnery, Elaine Walsh, Anna Maria Storniolo, Sara Tolaney, Nabihah Tayob, Antonio Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy Lin. The STOP-HER2 Trial: A Phase 2 Study of Stopping Trastuzumab - Outcomes in Patients with HER2+ Metastatic Breast Cancer (TBCRC 062) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-01.

Abstract Background In 2008, bevacizumab received accelerated Food and Drug Administration (FDA) approval for use in human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC). Based on the preclinical and preliminary clinical activity of the trastuzumab and bevacizumab combination, ECOG-ACRIN E1105 trial was developed to determine if the addition of bevacizumab to a chemotherapy and trastuzumab combination for first-line therapy would improve progression-free survival (PFS) in patients with HER2-positive MBC. Findings: 96 patients were randomized to receive standard first-line chemotherapy and trastuzumab with or without bevacizumab between November 2007 and October 2009, and 93 began protocol therapy. Induction therapy was given for 24 weeks, followed by maintenance trastuzumab with or without bevacizumab. 60% (56/93) began carboplatin and 74% (69/93) completed 6 cycles of induction therapy. Primary endpoint was PFS. Median PFS was 11.1 and 13.8 months for placebo and bevacizumab arms, respectively (hazard ratio [HR] 95%, Confidence Interval [Cl] for bevacizumab vs. placebo: 0.73 [0.43–1.23], p = 0.24), and at a median follow-up of 70.7 months, median survival was 49.1 and 63 months (HR [95% Cl] for OS: 1.09 [0.61–1.97], p = 0.75). The most common toxicities across both arms were neutropenia and hypertension, with left ventricular systolic dysfunction, fatigue, and sensory neuropathy reported more frequently with bevacizumab. Conclusions In this trial, the addition of bevacizumab did not improve outcomes in patients with metastatic HER2-positive breast cancer. Although the trial was underpowered due to smaller than anticipated sample size, these findings corroborated other clinical trials during this time.

Abstract Introduction Inflammatory bowel disease (IBD) is a chronic immune-mediated disease that includes Crohn’s disease and ulcerative colitis. People with IBD experience poor sleep health, including short and highly fragmented sleep and extraintestinal manifestations including alterations to cognitive functioning; however, the relationships between sleep health and cognitive symptoms have not been evaluated in this population. The purpose of this study was to identify the associations between sleep health and perceived cognitive impairments in adults with IBD. Methods We conducted a descriptive, correlational study of adults (18 to 59 years old) with IBD. We used the Pittsburgh Sleep Quality Index (PSQI) to obtain self-reported data on sleep health, the FACT-Cog Perceived Cognitive Impairments questionnaire to elicit cognitive symptoms, and the Manitoba IBD Index to describe IBD disease activity. Descriptive statistics, point-biserial correlations, and Pearson’s correlations were used to describe relationships. Results Of the 59 participants [Mean age 40.8 (SD 10.5), 71.2% female, 94.9% white], 67.8% (n=40) had clinically active IBD. 79.7% (n=47) had a PSQI total score >5, indicating poor sleep health. The most common cognitive symptoms, occurring two or more times a week, were trouble concentrating (55.9%), walking into a room and forgetting an intended task (44.1%), and forgetting the names of people soon after being introduced (44.0%). PSQI total score was positively and significantly correlated with 12 of 13 questions on the FACT-Cog. The strongest correlations included trouble concentrating (r = .497, P<.001), slower thinking (r = .450, p<.001), trouble forming thoughts (r=.550, p<.001), and difficulty finding the right words to express oneself (r=.546, p<.001). Longer self-reported sleep latency was associated with higher frequency of 12 out of 13 cognitive symptoms, while sleep efficiency was associated with 4 and sleep duration was associated with 2. Having clinically active IBD was associated with trouble forming thoughts (r=-.261, p=.046), slower thinking (r=-.307, p=.018), and trouble concentrating (r=-.346, p=.007). Conclusion Cognitive symptoms are common among people with IBD, highly correlated with sleep health, and not fully explained by IBD disease activity. Future studies should include objective measures of sleep health and cognition to further elucidate these relationships. Support (if any) Mayo Clinic Bonner Fund

Abstract Introduction Sleep disturbance and circadian rhythm disruptions are common among adults with chronic heart failure (HF), and are related to cognitive impairment. Although light levels are known to influence sleep quality, cognition, and the circadian system, little is known about the role of light among adults with HF. The purpose of this study is to investigate the association between light exposure and sleep, diurnal rest-activity rhythms (RAR), and cognitive function among adults with HF. Methods We retrospectively analyzed baseline data from a randomized controlled trial of cognitive behavioral therapy for insomnia for adults with HF and insomnia. We measured light levels and sleep with 24-hour wrist actigraphy and computed the circadian quotient, inter-daily stability, and intra-daily variability (strength of the RAR) using cosinor and non-parametric methods. We computed time above threshold (TAT) (100, 500, and 1000 lux), ratio of light exposure in daytime to evening (AUC ratio), and light regularity index (LRI) (20, 50, and 100 lux) to assess the intensity and consistency of light exposure patterns. Lapses in performance on the Psychomotor Vigilance Task (PVT lapse) measured cognitive function. Multiple linear regressions tested if the light exposure metrics could predict the RAR, sleep efficiency, and PVT lapses after adjusting for age, sex, and comorbidities. Results The sample included 167 participants (M age=63.8 (SD =12.9) years; 45.5%female). The AUC ratio and TAT500 were associated with a stronger circadian quotient in males (0.339 ± 0.095, p=.0005; 0.296 ± 0.085, p=.0006) compared to females (0.058 ± 0.106, p=.5800; -0.061 ± 0.128, p=.6364), after controlling for age and comorbidities. TAT500 was associated with better inter-daily stability (0.221 ± 0.077, p=.0044) than the other thresholds. Higher light exposure intensity (TAT100) (0.129 ± 0.065, p=.0492) and a greater circadian quotient (0.267±0.076, p=.0006) were associated with improved sleep efficiency. TAT100 was associated with fewer PVT lapses (-0.229 ± 0.082, p=.0061), after controlling for total sleep time, circadian quotient, and demographics. Conclusion Light exposure, particularly at certain intensities and regularity, predicted RARs, sleep efficiency, and cognitive function in adults with HF. Future tailored light interventions with varying intensities and regularity may improve HF outcomes. Support (if any)

Abstract Introduction Sleep disordered breathing (SDB: obstructive & central sleep apnea) and insomnia are common in heart failure (HF). However, most studies have not addressed the presence of combined SDB and insomnia (COMISA). The purposes of this study were to (1) describe COMISA among adults with stable chronic HF; (2) compare the clinical and demographic characteristics between groups with COMISA, insomnia, SDB, and normal sleep; and (3) examine the risk of COMISA in the presence of normal sleep, insomnia, SDB and other clinical and demographic characteristics. Methods Secondary analysis of an observational study of sleep among adults with stable HF. COMISA was defined as an apnea hypopnea index (AHI) > 15 with difficulty initiating or maintaining sleep or waking too early in the morning (Insomnia). We measured self-reported (Pittsburgh Sleep Quality Index) and objective sleep characteristics (polysomnography – PSG), symptoms (depression, sleepiness); used chi-square and ANOVA; and calculated the risks of COMISA for normal sleepers and with insomnia or SDB under different conditions (depression, poor sleep quality, left ventricular ejection fraction, age, race, and sex). Results The sample included 170 [(M age = 60.3 ± 16.8 years; n = 60 (35%] female. They had normal sleep (n = 37/22%); insomnia only (n = 48/28%): SDB only (n = 46/27%); and COMISA (n = 39/23%). Those with COMISA were significantly more likely to be obese (32.1%) compared to others [13.6% -29.6%, p = 0.0128]. They had the shortest total sleep time (TST) (mean = 291 ± 109 mins) and poorest sleep efficiency (M = 65.8 ± 20.5%) (p = .05). Women with insomnia were less likely to have COMISA than men (36% vs. 51%), while 74% of adults with SDB who were depressed had COMISA, compared with 41% of those with insomnia. Conclusion Risk of COMISA is associated with depression and poor sleep among adults with stable HF and SDB. Future study is needed to better understand the risks of COMISA among adults with chronic HF outcomes and to address the need for intervention that addresses it beyond a focus on only SDB or insomnia. Support (if any)

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator–activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

Abstract Although it is evident that standard-dose whole-brain radiotherapy as consolidation is associated with significant neurotoxicity, the optimal consolidative strategy for primary central nervous system lymphoma (PCNSL) is not defined. We performed a randomized phase 2 clinical trial via the US Alliance cancer cooperative group to compare myeloablative consolidation supported by autologous stem cell transplantation with nonmyeloablative consolidation after induction therapy for PCNSL. To our knowledge, this is the first randomized trial to be initiated that eliminates whole-brain radiotherapy as a consolidative approach in newly diagnosed PCNSL. Patients aged 18 to 75 years were randomly assigned in a 1:1 manner to induction therapy (methotrexate, temozolomide, rituximab, and cytarabine) followed by consolidation with either thiotepa plus carmustine and autologous stem cell rescue vs induction followed by nonmyeloablative, infusional etoposide plus cytarabine. The primary end point was progression-free survival (PFS). A total of 113 patients were randomized, and 108 (54 in each arm) were evaluable. More patients in the nonmyeloablative arm experienced progressive disease or death during induction (28% vs 11%; P = .05). Thirty-six patients received autologous stem cell transplant, and 34 received nonmyeloablative consolidation. The estimated 2-year PFS was higher in the myeloablative vs nonmyeloablative arm (73% vs 51%; P = .02). However, a planned secondary analysis, landmarked at start of the consolidation, revealed that the estimated 2-year PFS in those who completed consolidation therapy was not significantly different between the arms (86% vs 71%; P = .21). Both consolidative strategies yielded encouraging efficacy and similar toxicity profiles. This trial was registered at www.clininicals.gov as #NCT01511562.