Smith Clinic

Abstract Background: Breast cancer is the most common non-cutaneous malignancy among women, with around 10% of cases involving germline mutations in DNA repair genes. Germline mutations in BRCA1/2 genes significantly increase breast cancer risk. Other relevant genes to increase the risk of breast cancer include TP53, PTEN, PALB2, CHEK2, and ATM. Multigene panel testing can sequence many genes, sometimes identifying non-disease-related genes and variants of unknown significance. Methods: We reviewed patients with newly diagnosed breast cancer diagnosis from 2022 to 2024 in our institution. Germline genetic testing was offered to all newly diagnosed breast cancer patients at the time of diagnosis irrespective of their family history. Testing was offered to patients with invasive breast cancer and ductal carcinoma in situ. The goal of this study was to identify the prevalence of genes not attributed to increasing the risk of breast cancer and the implications of those results. Results: A total of 478 patients (Invasive cancer and DCIS) were seen in our oncology clinic from January 2022 to December 2024. The median age at diagnosis was 66 years (range 28-91). Invasive ductal cancer (IDC) was the most common subtype (66%), followed by DCIS (18%). Most patients had estrogen-positive cancer (81%), and approximately 14% had HER2-positive disease (62% HER2 low). We found 27 patients with pathogenic germline mutations which are not related to breast cancer risk. The most common mutation was MUYTH (7 patients), followed by FH gene (3 patients). MSH3, LZTR1, and HOXB13 genes were each found in 2 patients. APC, BAP1, BLM, BRIP1, NTHL1, SDHA, SDHB, MSH6, MITF, and FLCN genes were each identified in one patient. All patients with MUYTH mutations had hormone-positive (HER 2 negative) disease contrary to the limited observation of triple-negative breast cancer related to the MUYTH gene in the available literature. Patients with positive mutations were offered genetic counseling and referred to a high-risk genetics' clinic. FANCM was observed in one patient which has rarely been associated with an increased risk of triple-negative breast cancer. Conclusion: We present our single institution's experience of germline mutations in breast cancer patients. Previously, we observed CHEK2 being the most common breast cancer-related germline mutation in our patient population. This analysis focuses on identifying germline mutations without an increased risk of breast cancer. MUTYH was the most common pathogenic mutation identified. Further studies are needed to determine the actual risk percentage of breast cancer associated with the MUTYH gene. Universal testing for all breast cancer patients is feasible with the lower cost of multi-gene panels. However, identifying other non-disease-related genes, as observed in our study, has implications. Patients must be informed about the consequences of a positive result, including genetic counseling, additional screening tests, and testing of immediate family members. Citation Format: M. Zafar, M. Krishnakumar, A. Reddy. Non-breast cancer related germline mutations in breast cancer patients: a single institution experience [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-05-18.

In order to understand abnormal gait, this article will first review normal gait, discuss how neuromuscular diseases disturb gait patterns and review orthotic interventions. In normal gait, concentric contractions accelerate and eccentric contractions decelerate the limb. Neuromuscular gait disorders can be grouped into (1) proximal weakness, (2) distal weakness, (3) nonlength-dependent or generalized weakness, (4) asymmetric weakness, and (5) sensory disorders. Identification of gait disturbance type in neuromuscular diseases leads to the appropriate orthotic prescription since orthotic strategies are grouped into (1) proximal weakness, (2) distal weakness, and (3) sensory disturbances. Orthotics is not indicated in all types of gait disturbance. Weakness in proximal hip musculature can be managed with gait aids such as walkers. In contrast, distal muscle weakness can be managed with orthotics. Preservation of gait assists in maintenance of daily function and integration in society.

The abscopal effect describes tumor responses outside the irradiated field. The literature shows increased overall survival and response rates in patients receiving immunotherapy and radiation, likely from exaggerated abscopal effects. We present a 57-year-old woman with stage 4 lung adenocarcinoma who received treatment with a combination of chemotherapy and immunotherapy. She had disease progression on maintenance immunotherapy, confirming resistance. Palliative radiation to the sternal bone lesion resulted in a significant response to all areas of cancer, confirming the abscopal effect. Unfortunately, she developed severe pneumonitis; to our knowledge, this is the first case of abscopal lung toxicity.

LBA12007 Background: Practice guidelines recommend cardiovascular risk assessment and counseling for cancer survivors. The Automated Heart-Health Assessment study (AH-HA: WF-1804CD, NCT# 03935282) evaluated a novel electronic health record (EHR) clinical decision support tool based on American Heart Association Simple 7 cardiovascular health (CVH) factors to promote provider-patient CVH discussions in outpatient oncology. Methods: This clinic-randomized trial (R01CA226078), coordinated by the Wake Forest NCORP Research Base (UG1CA189824), randomized NCORP oncology practices using the Epic EHR to the AH-HA tool or usual care and enrolled survivors receiving routine care at least 6 months post-curative cancer treatment. The tool rendered an interactive display of risk factors, automatically populated from the EHR, alongside a tab indicating receipt of cancer treatments with cardiotoxic potential. Survivors at AH-HA sites had tool access during a routine visit; survivors at usual care sites did not. Immediately post-visit, each survivor was asked about counseling on 7 CVH factors [body mass index, physical activity, diet, smoking status, blood pressure, cholesterol, and glucose]. The primary endpoint is survivor-reported discussion of non-ideal or missing CVH factors; with 8 randomized practices (ICC=0.03), the study design had 82% power to detect a difference of 20% reported discussions in usual care versus 40% in AH-HA. Additional clinical endpoints were documentation of CVH discussions, referrals to primary care and cardiology, and change in CVH factors over 12 months (ongoing). A mixed effects logistic regression model assessed the effect of AH-HA on CVH discussions between the arms, with study arm as a fixed effect and practice as a random effect. Results: 5 usual care and 4 AH-HA practices enrolled 645 survivors from 10/1/2020- 2/28/2023. The majority had breast cancer (82%; 8% endometrial, 5% colorectal, 5% prostate, lymphoma or multiple types). Most survivors were female (96%; 84% White/non-Hispanic, 8% Black; 3% Hispanic; mean age= 62 yrs and median time since diagnosis=3.6 yrs). 18 participants (3%) did not complete necessary assessments, leaving 627 evaluable. 87% of providers (n=15) rated the tool utility and ease of use positively. Conclusions: The AH-HA tool was acceptable and effective at promoting CVH discussions during routine follow-up care for survivors and referrals to primary care. Clinical trial information: NCT03935282 . [Table: see text]

Diarrhea is a common symptom in medical practice that often gets overlooked. This article is intended to increase the awareness of physicians and other providers on a subtle but important cause of chronic diarrhea.

To characterize the effects of CSL112 (human APOA1 [apolipoprotein A1]) on the APOA1 exchange rate (AER) and the relationships with specific HDL (high-density lipoprotein) subpopulations when administered in the 90-day high-risk period post-acute myocardial infarction. A subset of patients (n=50) from the AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) study received either placebo or CSL112 post-acute myocardial infarction. AER was measured in AEGIS-I plasma samples incubated with lipid-sensitive fluorescent APOA1 reporter. HDL particle size distribution was assessed by native gel electrophoresis followed by fluorescent imaging and detection of APOA1 and SAA (serum amyloid A) by immunoblotting. CSL112 infusion increased AER peaking at 2 hours and returning to baseline 24 hours post-infusion. AER correlated with cholesterol efflux capacity (r=0.49), HDL-cholesterol (r=0.30), APOA1 (r=0.48), and phospholipids (r=0.48; all P<0.001) over all time points. Mechanistically, changes in cholesterol efflux capacity and AER induced by CSL112 reflected HDL particle remodeling resulting in increased small HDL species that are highly active in mediating ABCA1 (ATP-binding cassette transporter 1)-dependent efflux, and large HDL species with high capacity for APOA1 exchange. The lipid-sensitive APOA1 reporter predominantly exchanged into SAA-poor HDL particles and weakly incorporated into SAA-enriched HDL species. Infusion of CSL112 enhances metrics of HDL functionality in patients with acute myocardial infarction. This study demonstrates that in post-acute myocardial infarction patients, HDL-APOA1 exchange involves specific SAA-poor HDL populations. Our data suggest that progressive enrichment of HDL with SAA may generate dysfunctional particles with impaired HDL-APOA1 exchange capacity, and that infusion of CSL112 improves the functional status of HDL with respect to HDL-APOA1 exchange. URL: https://www. gov; Unique identifier: NCT02108262.

7003 Background: The role of alloHCT and subsequent maintenance for the treatment of high-risk MM has not been fully defined. We evaluated the efficacy of ixazomib maintenance therapy after alloHCT using reduced intensity fludarabine/melphalan/bortezomib (Flu/Mel/Bort)-based conditioning regimen to treat patients with high risk MM. Methods: This phase 2 prospective multicenter trial (NCT#02440464) enrolled adults 70 years or younger, with either high-risk MM defined by cytogenetics or plasma cell leukemia (PCL) or relapse within 24 months after autologous HCT. Conditioning regimen consisted of Flu/Mel/Bort. Patients received HLA-matched donor unmanipulated peripheral blood grafts. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus plus methotrexate. Between days +60 and +120 after allogeneic HCT, patients were randomly assigned (1:1, stratified by number of prior progressions) to receive ixazomib at 3 mg orally on days 1, 8, 15 on a 28-day cycle or matching placebo for 12 cycles. The study aimed to enroll 138 patients with 110 patients achieving randomization for a progression-free survival (PFS) comparison ixazomib maintenance vs. placebo. Results: Fifty-seven patients from 15 centers were enrolled (2015-18), of whom 52 (91.2%) received allogeneic HCT, and 43 (82.7%) proceeded to randomization (21 assigned to ixazomib and 22 to placebo). Enrollment was delayed by a clinical hold after enrollment of 17 patients due to toxicity concerns related to the conditioning regimen. Remaining patients were enrolled after an amendment reduced bort to a single pre-HCT dose. These and other delays in enrollment led to premature study closure. Median age was 56 (range, 35-65) years, and 33 patients (57.9%) had high-risk MM with 9 patients (15.8%) with primary PCL. At 24 mo post alloHCT, PFS and OS among all alloHCT recipients was 52% and 85% respectively with a corresponding transplant-related mortality (TRM) of 11%. At 21 mo post-randomization, ixazomib vs. placebo groups had similar PFS (55.3% vs. 59.1%) and OS (95% vs. 87%, p = 0.17). Cumulative incidences of grade III-IV acute GVHD at 100 days (9.5% vs. 0%) or chronic GVHD at 12 months (69% vs 64%) were similar. Best response, incidence of progression for ixazomib vs. placebo groups were similar while cumulative incidence of transplant-related mortality (TRM) at 21 months was 0.0% and 4.5% (90%CI: 0.5-16.5%), respectively. Conclusions: AlloHCT with reduced intensity fludarabine/melphalan and a single pre-HCT dose of bortezomib is safe and can produce durable disease control in extremely high-risk patients. ixazomib maintenance after alloHCT could not be assessed as intended due to early termination of study, but there was no signal of an impact in outcomes. Clinical trial information: NCT02440464.