High Risk Of Recurrence Research Articles

Outcomes in ovarian Sertoli-Leydig cell tumor: A report from the International Pleuropulmonary Blastoma/DICER1 and Ovarian and Testicular Stromal Tumor Registries

ObjectiveSertoli-Leydig cell tumors (SLCTs) are rare sex cord-stromal tumors, representing <0.5% of all ovarian tumors. We sought to describe prognostic factors, treatment and outcomes for individuals with ovarian SLCT. MethodsIndividuals with SLCT were enrolled in the International Pleuropulmonary Blastoma/DICER1 Registry and/or the International Ovarian and Testicular Stromal Tumor Registry. Medical records were systematically abstracted, and pathology was centrally reviewed when available. ResultsIn total, 191 participants with ovarian SLCT enrolled, with most (92%, 175/191) presenting with FIGO stage I disease. Germline DICER1 results were available for 156 patients; of these 58% had a pathogenic or likely pathogenic germline variant. Somatic (tumor) DICER1 testing showed RNase IIIb hotspot variants in 97% (88/91) of intermediately and poorly differentiated tumors. Adjuvant chemotherapy was administered in 40% (77/191) of cases, and among these, nearly all patients received platinum-based regimens (95%, 73/77), and 30% (23/77) received regimens that included an alkylating agent. Three-year recurrence-free survival for patients with stage IA tumors was 93.6% (95% CI: 88.2–99.3%) compared to 67.1% (95% CI: 55.2–81.6%) for all stage IC and 60.6% (95% CI: 40.3–91.0%) for stage II-IV (p < .001) tumors. Among patients with FIGO stage I tumors, those with mesenchymal heterologous elements treated with surgery alone were at higher risk for recurrence (HR: 74.18, 95% CI: 17.99–305.85). ConclusionMost individuals with SLCT fare well, though specific risk factors such as mesenchymal heterologous elements are associated with poor prognosis. We also highlight the role of DICER1 surveillance in early detection of SLCT, facilitating stage IA resection.

Silver-Russell syndrome-like features in a child with recombinant chromosome 11 derived from maternal pericentric inversion.

Silver-Russell syndrome (SRS) is a well-known syndrome but with heterogeneous etiologies. We present the case of a child with severe SRS-like features resulting from a complex rearrangement of chromosome 11 inherited from his mother. We studied the index case with karyotyping, MS-MLPA and molecular karyotyping. The mother was studied with karyotyping and subtelomeric FISH. We found a child with marked developmental delay and fatal outcome due to failure to thrive, carrying an 11p15 duplication and an 11q25 deletion of maternal origin. We discovered that the mother was a carrier of a pericentric inversion of chromosome 11, with a history of recurrence in other family members who had severe growth retardation and early death. To our knowledge, no similar SRS-like cases have been described in the literature. This report supports the importance of identification the causative genetic mechanism in SRS-like individuals with duplication in 11p15 region due to high risk of recurrence and to provide an appropriate genetic counseling to the family.

Radiofrequency Catheter Ablation for Atrial Fibrillation Patients on Hemodialysis (From the Kansai Plus Atrial Fibrillation Registry) - Clinical Impact of Early Recurrence.

Catheter ablation (CA) for atrial fibrillation (AF) in patients on hemodialysis (HD) is reported to have a high risk of late recurrence (LR). However, the relationship between early recurrence (ER) within a 90-day blanking period after CA in AF patients and LR in HD patients remains unclear.Methods and Results: Of the 5,010 patients in the Kansai Plus Atrial Fibrillation Registry, 5,009 were included in the present study. Of these patients, 4,942 were not on HD (non-HD group) and 67 were on HD (HD group). HD was an independent risk factor for LR after the initial CA (adjusted hazard ratio 1.6; 95% confidence interval 1.1-2.2; P=0.01). In patients with ER, the rate of sinus rhythm maintenance at 3 years after the initial CA was significantly lower in the HD than non-HD group (11.4% vs. 35.4%, respectively; log-rank P=0.004). However, in patients without ER, there was no significant difference in the rate of sinus rhythm maintenance at 3 years between the HD and non-HD groups (67.7% vs. 74.5%, respectively; log-rank P=0.62). ER in HD patients was a strong risk factor for LR. However, even HD patients could expect a good outcome without ER after the initial CA.

Pathophysiology, Diagnosis, Prognosis, and Prevention of Poststroke Epilepsy: Clinical and Research Implications.

Poststroke epilepsy (PSE) is associated with higher mortality and poor functional and cognitive outcomes in patients with stroke. With the remarkable development of acute stroke treatment, there is a growing number of survivors with PSE. Although approximately 10% of patients with stroke develop PSE, given the significant burden of stroke worldwide, PSE is a significant problem in stroke survivors. Therefore, the attention of health policymakers and significant funding are required to promote PSE prevention research. The current PSE definition includes unprovoked seizures occurring more than 7 days after stroke onset, given the high recurrence risks of seizures. However, the pathologic cascade of stroke is not uniform, indicating the need for a tissue-based approach rather than a time-based one to distinguish early seizures from late seizures. EEG is a commonly used tool in the diagnostic work-up of PSE. EEG findings during the acute phase of stroke can potentially stratify the risk of subsequent seizures and predict the development of poststroke epileptogenesis. Recent reports suggest that cortical superficial siderosis, which may be involved in epileptogenesis, is a promising marker for PSE. By incorporating such markers, future risk-scoring models could guide treatment strategies, particularly for the primary prophylaxis of PSE. To date, drugs that prevent poststroke epileptogenesis are lacking. The primary challenge involves the substantial cost burden due to the difficulty of reliably enrolling patients who develop PSE. There is, therefore, a critical need to determine reliable biomarkers for PSE. The goal is to be able to use them for trial enrichment and as a surrogate outcome measure for epileptogenesis. Moreover, seizure prophylaxis is essential to prevent functional and cognitive decline in stroke survivors. Further elucidation of factors that contribute to poststroke epileptogenesis is eagerly awaited. Meanwhile, the regimen of antiseizure medications should be based on individual cardiovascular risk, psychosomatic comorbidities, and concomitant medications. This review summarizes the current understanding of poststroke epileptogenesis, its risks, prognostic models, prophylaxis, and strategies for secondary prevention of seizures and suggests strategies to advance research on PSE.

Postoperative Crohn's Disease Recurrence Risk and Optimal Biologic Timing After Temporary Diversion Following Ileocolic Resection.

Postoperative recurrence of Crohn's disease (CD) is common. While most patients undergo resection with undiverted anastomosis (UA), some individuals also have creation of an intended temporary diversion (ITD) with an ileostomy followed by ostomy takedown (OT) due to increased risk of anastomotic complications. We assessed the association of diversion with subsequent CD recurrence risk and the influence of biologic prophylaxis timing to prevent recurrence in this population. This was a retrospective cohort study of CD patients who underwent ileocolic resection between 2009 and 2020 at a large quaternary health system. Patients were grouped by continuity status after index resection (primary anastomosis or ITD). The outcomes of the study were radiographic, endoscopic, and surgical recurrence as well as composite recurrence postoperatively (after OT in the ITD group). Propensity score-weighted matching was performed based on risk factors for diversion and recurrence. Multivariable regression and a Cox proportional hazards model adjusting for recurrence risk factors were used to assess association with outcomes. Subgroup analysis in the ITD group was performed to assess the impact of biologic timing relative to OT (no biologic, biologic before OT, after OT) on composite recurrence. A total of 793 CD patients were included (mean age 38 years, body mass index 23.7kg/m2, 52% female, 23% active smoker, 50% penetrating disease). Primary anastomosiswas performed in 67.5% (n = 535) and ITD in 32.5% (n = 258; 79% loop, 21% end) of patients. Diverted patients were more likely to have been males and to have had penetrating and perianal disease, prior biologic use, lower body mass index, and lower preoperative hemoglobin and albumin (all P < .01). After a median follow-up of 44 months, postoperative recurrence was identified in 83.3% patients (radiographic 40.4%, endoscopic 39.5%, surgical 13.3%). After propensity score matching and adjusting for recurrence risk factors, no significant differences were seen between continuity groups in radiographic (adjusted hazard ratio [aHR], 1.32; 95% confidence interval [CI], 0.91-1.91) or endoscopic recurrence (aHR, 1.196; 95% CI, 0.84-1.73), but an increased risk of surgical recurrence was noted in the ITD group (aHR, 1.61; 95% CI, 1.02-2.54). Most (56.1%) ITD patients started biologic prophylaxis after OT, 11.4% before OT, and 32.4% had no postoperative biologic prophylaxis. Biologic prophylaxis in ITD was associated with younger age (P < .001), perianal disease (P = .04), and prior biologic use (P < .001) but not in recurrence (P = .12). Despite higher rates of objective disease activity identified before OT, biologic exposure before OT was not associated with a significant reduction in composite post-OT recurrence compared with starting a biologic after OT (52% vs 70.7%; P = 0.09). Diversion of an ileocolic resection is not consistently associated with a risk of postoperative recurrence and should be performed when clinically appropriate. Patients requiring diversion at time of ileocolic resection are at high risk for recurrence, and biologic initiation prior to stoma reversal may be considered.

Multivariable prognostic modelling to improve prediction of colorectal cancer recurrence: the PROSPeCT trial.

Improving prognostication to direct personalised therapy remains an unmet need. This study prospectively investigated promising CT, genetic, and immunohistochemical markers to improve the prediction of colorectal cancer recurrence. This multicentre trial (ISRCTN 95037515)recruited patients with primary colorectal cancer undergoing CT staging from 13 hospitals. Follow-up identified cancer recurrence and death. A baseline model for cancer recurrence at 3 years was developed from pre-specified clinicopathological variables (age, sex, tumour-nodestage, tumoursize, location, extramural venous invasion, and treatment). Then, CT perfusion (blood flow, blood volume,transit time and permeability), genetic (RAS, RAF, and DNA mismatch repair), and immunohistochemical markers of angiogenesis and hypoxia (CD105, vascular endothelial growth factor, glucose transporter protein, and hypoxia-inducible factor) were added to assess whether prediction improved over tumour-node staging alone as the main outcome measure. Three hundred twenty-six of 448 participants formed the final cohort (226 male; mean 66 ± 10 years. 227 (70%) had ≥ T3 stage cancers; 151 (46%) were node-positive; 81 (25%) developed subsequent recurrence. The sensitivity and specificity of staging alone for recurrence were 0.56 [95% CI: 0.44, 0.67] and 0.58 [0.51, 0.64], respectively. The baseline clinicopathologic model improved specificity (0.74 [0.68, 0.79], with equivalent sensitivity of 0.57 [0.45, 0.68] for high vs medium/low-risk participants. The addition of prespecified CT perfusion, genetic, and immunohistochemical markers did not improve prediction over and above the clinicopathologic model (sensitivity, 0.58-0.68; specificity, 0.75-0.76). A multivariable clinicopathological model outperformed staging in identifying patients at high risk of recurrence. Promising CT, genetic, and immunohistochemical markers investigated did not further improve prognostication in rigorous prospective evaluation. A prognostic model based on clinicopathological variables including age, sex, tumour-node stage, size, location, and extramural venous invasion better identifies colorectal cancer patients at high risk of recurrence for neoadjuvant/adjuvant therapy than stage alone. Identification of colorectal cancer patients at high risk of recurrence is an unmet need for treatment personalisation. This model for recurrence, incorporating many patient variables, had higher specificity than staging alone. Continued optimisationof risk stratification schema will help individualise treatment plans and follow-up schedules.

PREDICTORS OF METALWORK FAILURE AND NONUNION AFTER HINDFOOT CHARCOT RECONSTRUCTION

IntroductionSurgical reconstruction of deformed Charcot feet carries high risk of non-union, metalwork failure and deformity recurrence. The primary aim of this study was to identify the factors contributing to these complications following hindfoot Charcot reconstructions.MethodsWe retrospectively analysed patients who underwent hindfoot Charcot reconstruction with an intramedullary nail between 2007 and 2019 in our unit. Patient demographics, co-morbidities, weightbearing status and post-operative complications were noted. Metalwork breakage, non-union, deformity recurrence, concurrent midfoot reconstruction and the measurements related to intramedullary nail were also recorded.ResultsThere were 70 patients with mean follow up of 50±26 months. Seventy-two percent were fully weightbearing at 1 year post-operatively. The overall union rate was 83%. Age, BMI, HbA1c and peripheral vascular disease did not affect union. The ratio of nail diameter and isthmus was greater in the united compared to the non-united group (0.90±0.06 and 0.86±0.09, respectively; p = 0.03). Supplemental compression devices were used for 33% of those in the united compared to 8% in the non-united group (p = 0.04). All patients in the non-union group did not have a miss-a-nail screw. Metalwork failure was seen in 13 patients(19%). There was a significantly greater distal screw metalwork failure in those with supplementary bridging of tibia to midfoot (23% vs. 3%; p = 0.001). An intact medial malleolus was found more frequently in those with intact metalwork (77% vs. 54%, respectively; p = 0.02) and those with union (76% vs. 50%; p = 0.02). Broken metalwork occurred more frequently in patients with non-unions (69% vs. 8%; p &lt; 0.001) and deformity recurrence (69% vs. 9%; p &lt; 0.001).ConclusionSatisfactory clinical and radiographic outcomes occur in over 80% of patients. Union after hindfoot reconstruction occurs more frequently with an isthmic fit of the intramedullary nail, supplementary compression and miss-a-nail screws. An intact medial malleolus is protective against non-union and metalwork failure. Broken metalwork is linked to deformity recurrence and non-union.

Ten-year prognosis of acute atrial fibrillation in ST-elevation myocardial infarction: recurrence and risk stroke.

Atrial fibrillation (AF) often complicates ST elevation acute myocardial infarction (STEMI), with associated risks including stroke and mortality. Anticoagulation therapy for these patients and AF prognosis remains controversial. The aim was to evaluate long-term prognosis of STEMI patients complicated with AF in the acute phase. We performed a retrospective analysis on a prospective register involving 4,184 patients admitted for STEMI to the intensive cardiac care unit of 2 tertiary centres from 2007 to 2015. Patients with pre-existing permanent AF were excluded. Out of these, 269 (6.4%) patients developed AF within the first 48 hours after STEMI and were matched with a control group based on age and left ventricular ejection fraction (LVEF). After matching, a total of 470 patients were included (n=235, AF-STEMI; n=235, control group). Mean age 69.0 years, and 31.7% women. No differences were found in gender, cardiovascular risk factors or ischemic heart disease. AF-STEMI patients experienced more sustained ventricular tachycardia, advanced atrioventricular block, heart failure, and cardiogenic shock. In-hospital mortality was also higher in AF-STEMI patients (11.9% vs 7.2%, p=0.008). After 10-years follow-up, the AF-STEMI group had remained with higher mortality (50.5% vs. 36.2%; p=0.003) and a greater recurrence of AF (44.2% vs. 14.7%; p<0.001), without differences in stroke incidence (10.1% vs. 9.3%). As a conclusion, patients with AF complicating STEMI have higher rates of heart failure, cardiogenic shock, and in-hospital mortality. After a 10-year follow-up, they exhibit a high risk of AF recurrence and mortality, with no significant differences in stroke incidence.

Topographic modification of the extracellular matrix precedes the onset of bladder cancer

BackgroundNon-muscle invasive bladder cancer (NMIBC) patients are affected by a high risk of recurrence. The topography of collagen fibers represents a hallmark of the neoplastic extracellular microenvironment. ObjectiveAssess the topographic change associated with different stages of bladder cancer (from neoplastic lesions to bona fide tumor) and whether those changes favour the development of NMIBC. Design, Setting, and ParticipantsSeventy-one clinical samples of urothelial carcinoma at different stages were used. Topographic changes preceding tumor onset and progression were evaluated in the rat bladder cancer model induced by nitrosamine (BBN), a bladder-specific carcinogen. The preclinical model of actinic cystitis was also used in combination with BBN. Validated hematoxylin-eosin sections were used to assess the topography of collagen fibrils associated with pre-tumoral steps, NMIBC, and MIBC. FindingsLinearization of collagen fibers was higher in Cis and Ta vs. dysplastic urothelium, further increased in T1 and greatest in T2 tumors. In the BBN preclinical model, an increase in the linearization of collagen fibers was established since the beginning of inflammation, such as the onset of atypia of a non-univocal nature and dysplasia, and further increased in the presence of the tumor. Linearization of collagen fibers in the model of actinic cystitis was associated with earlier onset of BBN-induced tumor. ConclusionsThe topographic modification of the extracellular microenvironment occurs during the inflammatory processes preceding and favoring the onset of bladder cancer. The topographic reconfiguration of the stroma could represent a marker for identifying and treating the non-neoplastic tissue susceptible to tumor recurrence.

Adjuvant donafenib for patients with hepatocellular carcinoma at high risk of recurrence following radical resection: A multi-center, retrospective study in China.

e15129 Background: The implementation of adjuvant therapy in reducing tumor recurrence of hepatocellular carcinoma (HCC) is an essential approach for extending the prognosis of patients. The exploration of treatment strategies that are both efficacious and secure remains a prominent area of research in recent years. Donafenib is a novel, oral, small-molecule, multikinase inhibitor, and has demonstrated promising efficacy and safety profiles in preclinical and clinical studies. However, there is currently a lack of reported data on the adjuvant donafenib for HCC following radical resection (R0). The present study aimed to explore the efficacy and safety of adjuvant donafenib for HCC patients at high risk of recurrence following R0. Methods: This retrospective study analyzed 196 patients who underwent R0 for HCC between April 2021 and October 2022. All patients exhibited at least one of the following high risk recurrence factors:① single lesion &gt; 5 cm or multiple lesions of any size; ② microvascular invasion (MVI); and ③ satellite nodules. Among these patients, 49 received donafenib, while 147 (control group) did not. In the donafenib group, donafenib was administered at a dose of 100 or 200 mg bid until tumor recurrence and serious adverse events (AEs). The 1-year and 2-year recurrence-free survival (RFS) rates and overall survival (OS) rates were compared between the two groups, as well as the incidence of adverse events (AEs) in the donafenib group. Inverse probability of treatment weighting (IPTW) was used. Results: The patient population consisted of 167 males and 29 females, with a median age of 59 (range 30-83). All patients exhibited a high risk of recurrence (number of tumors single/multiple, 167/29; tumor size within 5.0/above 5.0 cm, 78/118; MVI yes/no, 140/56; satellite nodules yes/no, 39/157). The median follow-up was 21.8 (range 3.8-32.0) months. Before IPTW, the donafenib group exhibited significantly higher 1-year and 2-year RFS rates compared to the control group (83.7%, 68.0% vs 66.7%, 47,6%, p = 0.023), while no significant difference in 1-year and 2-year OS rates (97.8%, 93.9% vs 91.8%, 80.6%, p = 0.120). After IPTW, the 1-year, 2-year RFS rates and OS rates were more favorable for the donafenib group compared to the control group (86.6%, 72.5% vs 64.8%, 45.0%, P = 0.004; 97.9%, 95.6% vs 89.5%, 77.9%, P = 0.043, respectively). In the donafenib group, AEs occurred in 44 patients, including 39 with grade 1 or 2 AEs and 5 with grade 3 AEs. The most common AEs included hand-foot skin reaction, decreased platelet count, and diarrhea. Conclusions: Adjuvant donafenib may improve RFS of HCC patients at high risk of recurrence following R0, while exhibiting favorable safety. This finding deserves further exploration.

CtDNA monitoring for breast cancer at high risk of recurrence: Interim analysis of JCOG1204A1.

518 Background: Monitoring ctDNA after definitive surgery has emerged as an accurate predictor of breast cancer (BC) recurrence. However, further data is needed to determine the proportion and dynamics of ctDNA positivity in different BC subtypes. Here we present ctDNA status and dynamics in patients from an ancillary study (A1) of the prospective randomized phase III JCOG1204 trial (UMIN000012429; Registration: November 2013 - January 2020, N = 1034) in which intensive post-operative follow-up is compared to standard follow-up in BC patients at high risk of recurrence. Methods: Eligible patients enrolled in JCOG1204 were required to have either (1) ≥4 lymph node metastases for estrogen receptor (ER)+ BC without neoadjuvant therapy, (2) ≥1 lymph node metastases for ER- without neoadjuvant therapy, or (3) ≥1 lymph node metastases after neoadjuvant therapy. Additional inclusion criteria for ancillary study JCOG1204A1 include no more than 4 years after surgery and relapse-free at the enrollment. A personalized, tumor-informed assay (Signatera, Natera Inc.) was used for ctDNA surveillance every 3 - 6 months for 2 years for ER- or 5 years for ER+ BC. ctDNA status, time of ctDNA detection and association with subtype were examined. The JCOG DSMC approved the publication of this interim analysis. Results: A total of 248 patients were enrolled (July 2020-October 2023) in JCOG1204A1. Personalized assays were successfully designed for 88% patients, the main reason for failure was insufficient tissue (83%; 25/30). A total of 1440 plasma ctDNA samples were collected from 211 patients. The median age at the time of surgery was 50 years. The most prevalent subtype was ER+ HER2- (Luminal; n = 130), followed by ER- HER2- (TN; n = 38), ER- HER2+ (HER2; n = 24), and ER+ HER2+ (Luminal-HER2; n = 18). 25 patients (11.8%) had at least one positive ctDNA result, with overall sample-level positivity proportion of 4.5% (65 / 1440); 76% (19/25) became detectable with longitudinal testing. Surveillance in TN [the first time point median 31.5 months (12.6-55.8) from surgery] did not result in ctDNA detection. Of the 130 patients with Luminal subtype [the first time point median 36.6 months (12-57) from surgery], 21 (16.2%) had ctDNA first detected at a median 43.5 months (18-72). Additionally, 5 patients (2.4%) had ctDNA detection for the first time after 5 years of surgery. The proportion of ctDNA positivity increased by ~2% annually in Luminal subtype; varied rates of ctDNA level increase have been observed. Conclusions: Monitoring ctDNA in high-risk BC reveals a detection proportion of 11.8% at the patient level (TNBC: 0%; Luminal: 16.2%) Longitudinal testing revealed ctDNA detection in patients with luminal subtype beyond 5 years from surgery, suggesting a correlation with late recurrence. Subsequent reports will focus on investigating the association of ctDNA status with relapse and overall survival.

Breast cancer polygenic risk score and patient survival outcomes in the Pathways study.

10502 Background: Many common, low-penetrance variants have been identified for breast cancer risk through genome-wide association studies, leading to the development of polygenic scores (PGS) to aggregate the effects of individual variants for risk prediction. Much less is known about genetic determinants of breast cancer-related outcomes. We hypothesized that breast cancer patients with high breast cancer PGS are at risk of a second breast-related adverse event, such as recurrence, contralateral breast cancer, or death. Methods: The Pathways Study is a prospective cohort study of breast cancer survivors enrolled shortly after diagnosis in 2006-2013 at Kaiser Permanente Northern California, with ongoing follow-up. Genome-wide genotype data were available from 3,995 patients for calculation of 4 PGS, including PGS313, PGS4k, PGS5k, and PGS6m. Scores were categorized into tertiles to investigate their associations with 7 survival outcomes including recurrence, contralateral second primary breast cancer, other second primary cancer, and death. Hazard ratios (HR) and 95% confidence intervals (CI) were derived from multivariable Cox proportional hazards regression models. Results: The median age at diagnosis was 60 (23.6-94.8) years, and most (68%) self-identified as White. Many women had estrogen receptor (ER)+ (83.4%), stage I and II tumors (89%), with 13.3% HER2+ tumors. The majority (60%) received lumpectomy and some type of adjuvant therapy (44.3% radiotherapy, 47.0% chemotherapy, and 74.6% received hormonal therapy). By December 31, 2021, the median follow-up time was 10.5 (0.2-14.2) years, with 504 recurrences, 419 total second primary cancers, 146 contralateral second primary breast cancers, 237 non-breast second primary cancers, and 762 deaths (352 breast cancer-specific deaths) observed. In Table 1, patients with medium (T2) and high (T3) PGS313 had higher risk of recurrence, but not contralateral breast cancer or other second primary cancer. They also had higher risk of all-cause death, breast cancer-specific death, total breast cancer event, and invasive disease. The other 3 PGS were not associated with survival outcomes examined. Conclusions: Our study reveals that breast cancer patients with higher PGS313 had higher risk of recurrence, total breast cancer and invasive breast cancer events, and death. These findings highlight a potential role of breast cancer PGS for prognosis, warranting further exploration. [Table: see text]

TBCRC 058: A randomized phase II study of enzalutamide, enzalutamide with mifepristone, and treatment of physician’s choice in patients with androgen receptor-positive metastatic triple-negative or estrogen receptor-low breast cancer (NCT06099769).

TPS1138 Background: Triple-negative breast cancer (TNBC) refers to a heterogenous group of breast cancers that lack expression of ER, PR, and HER2. Despite recent advances with immunotherapy (IO) and antibody-drug conjugates (ADCs), TNBC remains the most aggressive subtype, characterized by a high risk of recurrence and a short overall survival in the metastatic setting. Breast tumors with low levels of ER and PR expression (1-10%) clinically behave like TNBC, and clinical management follows the TNBC treatment (tx) paradigm. We and others have identified a subset of ER/PR/HER2 negative breast cancers (BC) that express the androgen receptor (AR). Enzalutamide (enza), an AR-antagonist, has demonstrated activity in AR+ metastatic TNBC (Traina et al, JCO 2018). Activation of the glucocorticoid receptor (GR) has been implicated as a mechanism of resistance to AR inhibition in prostate and BCs (Kach et al, Sci Transl Med 2015). Effective therapies for advanced TNBC remain an unmet need, particularly in patients who are ineligible for or progress following a checkpoint inhibitor. This randomized study will evaluate the efficacy of enzalutamide or enzalutamide plus the GR antagonist mifepristone (mif) as compared to physician’s choice chemotherapy (TPC). Methods: This is a randomized phase II trial; 201 patients (pts) will be randomized in a 1:1:1 fashion to enza, enza with mif, or TPC (carboplatin, paclitaxel, eribulin, or capecitabine). The primary endpoint (endpt) is progression free survival (PFS), and the trial is designed to test the hypothesis that PFS in the pooled enzalutamide arms is superior to TPC; there is 80% power to detect a hazard ratio (HR) of 0.70, corresponding to increase in PFS from 3.5 months (mos) with TPC to 5.0 mos with enza-based tx. Secondary endpts include comparisons of PFS among 3 arms and evaluation of response rate, clinical benefit rate, duration of response, overall survival, safety/toxicity, and patient-reported outcomes by arm. Exploratory endpts include correlation of tumor and circulating markers (constitutively active AR variants in circulating tumor cells and circulating tumor cell DNA) with tx response. Eligible pts must have: ECOG 0-2, metastatic ER/PR low or negative, HER2 negative breast cancer (BC), measurable or evaluable disease (dz), &lt; 2 prior lines of chemotx, any # prior endocrine txs, no prior anti-AR tx, no prior mif, concurrent CYP17 inhibitors prohibited. Pts with PD-L1+ BC must have received prior IO if not contraindicated. Tumors must have AR ≥10%, normal organ function, no history of brain mets. As of 1/15/2024, 2 of 201 pts have begun protocol-specified tx. Clinical trial information: NCT06099769 .

Real world outcomes of 2,339 patients with early-stage triple-negative breast cancer (TNBC) treated in British Columbia.

e23274 Background: TNBC represents 15-20% of all breast cancers, and tends to exhibit more aggressive features, more frequent distant metastasis and overall worse prognosis than other breast cancer subtypes. The treatment landscape for early-stage TNBC has changed considerably in the last decade, with new additions to neoadjuvant therapy (NAT) aimed at improving pathologic responses and outcomes. In this study, we assess real world data regarding treatment and outcomes in those with early-stage TNBC. Methods: The BC Cancer Breast Cancer Outcomes Unit database contains prospectively collected data on patients residing in British Columbia and diagnosed with breast cancer since 1989. This retrospective study evaluated patients diagnosed with stage I-III TNBC from 2010 to 2019. During this era, regimens containing anthracyclines and taxanes were routinely used. TNBC was defined as per ASCO-CAP guidelines as ER≤1%, PR≤1% and negative HER 2 (0, 1+ by immunohistochemistry, or 2+ ISH negative). Outcomes of interest included event free survival (EFS), overall survival (OS), and pathologic complete response (pCR). Results: 2,339 patients withstage I-III TNBC were identified with a mean follow up of 6.5 years. OS was 87% (95% CI 85-88%) at 3-years and 79% (95% CI 77-80%) at 5-years. The presenting stage was a significant prognostic factor, with 5-year EFS of 89%, 81% and 51%- and 5-year OS of 90%, 80%, and 53% for stages I, II, and III, respectively. There was an increase in NAT use in 2019 (n = 82/230,35.7%) when compared to 2010 (n = 20/227, 8.8%). The most common neoadjuvant regimens used included anthracycline and taxane chemotherapies (n = 343,81.4%), with only a small number receiving neoadjuvant platinum chemotherapy (n = 52, 12.4%). Pathological complete response (pCR) was achieved in 24.5% (103/421) of patients who received NAT. Patients with pCR had improved 5- year EFS (91% vs. 57%, HR 0.26 [95% CI 0.15-0.45]) and 5-year OS (90% vs. 59%, HR 0.26 [95% CI 0.15-0.45]) compared to those with residual disease. The subgroup that received salvage capecitabine had a poor 3-year EFS at 22% but was enriched for patients with residual nodal disease after NAT (n = 77/130, 59.2%). Conclusions: This real-world study of TNBC in the era prior to routine immunotherapy (IO), highlights the poor prognosis of TNBC, particularly patients with locally advanced disease and those who did not achieve pCR, despite adjuvant capecitabine. This stresses the need for advances in NAT and salvage therapies for TNBC with residual disease at high risk of recurrence. [Table: see text]

Harnessing cell-free orphan non-coding RNAs as a predictive measure of long-term survival in neoadjuvant breast cancer therapy.

585 Background: Pathologic complete response (pCR) is a valuable metric for predicting survival following neoadjuvant therapy (NAT) in breast cancer; however, blood-based biomarkers may refine the prediction of treatment outcomes and inform follow-up treatment decisions. Orphan non-coding RNAs (oncRNAs) are a novel category of small RNAs that are present in tumors and largely absent in healthy tissue. Here, we explore the feasibility of a tumor-naive oncRNA-based liquid biopsy assay for predicting distant recurrence-free survival (DRFS) in breast cancer patients using a standard blood draw. Methods: Our cohort included 538 high-risk breast cancer patients from the multicenter I-SPY2 trial having serum available after NAT and before surgery (timepoint T3). Of the 538 patients (mean age: 48.8 ± 10.3), 191 (36%) achieved pCR. We isolated small RNA from 0.8 mL of patient serum and sequenced it at an average depth of 50 million 100-bp single-end reads. We used our catalog of tumor-derived oncRNAs, discovered in The Cancer Genome Atlas, to develop an AI model for predicting tumor burden based on tumor size. Our AI model was trained on oncRNA profiles from an independent cohort of 719 serum samples collected at diagnosis from individuals with cancer. We assessed tumor burden by oncRNA in the I-SPY2 cohort at T3 and associated this measure with DRFS using robust cutpoints established for each of the two pCR groups: high- ( n=70) and low-burden ( n=468) cutpoints were verified through cross-validation and almost all folds converged on a single value, which we used in our analysis. Results: The continuous oncRNA-derived tumor burden at T3 had a hazards ratio (HR) of 2.4 (95% CI: 1.1–5.1) for predicting DRFS. This measure remained significant in multivariate Cox models that included pCR (HR = 2.7 [1.3–5.6]) or residual cancer burden (RCB II/III versus 0/I; HR = 3.4 [1.6–7.1]). Patients with pCR had a 3-year DRFS of 94%; patients with pCR having low ( n=180) versus high ( n=11) oncRNA burden resulted in 95% and 73% 3-year DRFS, respectively (HR = 7.4 [2.3–24]). Those without pCR had a 3-year DRFS of 78% and stratification by oncRNA burden resulted in 85% and 71% 3-year DRFS for the low ( n=288) and high ( n=59) burden groups, respectively (HR=2.4 [1.5–3.9]). Importantly, we saw no restricted mean survival time difference (RMST) at 3 years between those with and without pCR among the high oncRNA burden group (0.1-month difference, p=0.97). Conclusions: We demonstrate the utility of a tumor-naive, oncRNA-derived tumor burden AI model as a predictive measure of treatment outcome and as a prognostic biomarker that can be used in addition to pCR to further stratify patients as low or high risk of recurrence. Integration of our oncRNA assay with existing biomarkers and clinicopathologic variables, has the potential to add value for predicting outcomes and prioritizing patients that would benefit from additional care.

Predicting response to neoadjuvant therapy (NAT) in patients (pts) with early-stage breast cancer (BC) using circulating tumor DNA (ctDNA) testing.

569 Background: Recent studies have shown the utility of ctDNA testing for monitoring response and predicting long term outcomes in pts with BC receiving NAT. This pilot, single institution study (CIPHER, NCT05333874) evaluated whether trend of ctDNA during NAT can serve as an early indicator of treatment response and inform disease management in the adjuvant setting. Methods: This study included 35 pts with stage II-III triple negative (TN) and HER2+ BC and longitudinal ctDNA testing performed during standard of care NAT. A clinically validated, personalized, tumor-informed 16-plex PCR assay (Signatera) was used for the detection and quantification of ctDNA in blood samples collected at diagnosis (pre-treatment), every 3 weeks on NAT, and post-surgery. ctDNA status and dynamics were correlated with clinicopathological features and surgical outcomes. Results: At diagnosis (N=30), ctDNA was detected in 95% (18/19) of pts with TNBC [median 8.89 (0.09-180.01) mean tumor molecules (MTM)/mL] and 91% (10/11) of pts with HER2+ BC [median 1.55 (0.29-453.86) MTM/mL], including 73% (8/11) pts with HR+/HER2+ BC. ctDNA detection rate was higher in pts with clinical T3-4 disease compared to T1-2 (TNBC: 4/4, 100% vs 14/15, 93%; HER2+ BC: 4/4, 100% vs 6/7, 86%). Similarly, higher median pre-treatment ctDNA levels were observed in pts with clinical T3-4 compared to T1-2 (TNBC 61.49 vs 9.28 MTM/mL; HER2+ BC 14.94 vs 1.18 MTM/mL). Pts with early ctDNA clearance (&lt;6 weeks of NAT) had a higher proportion of favorable surgical outcomes (pCR or &lt;1 cm, node negative) compared to pts with late (&gt;6 weeks) or no clearance during NAT (17/20, 85% vs 4/6, 67%). Post-surgical ctDNA-positivity was observed in 5% (1/19) vs 67% (4/6) pts with early vs late/no clearance during NAT, respectively. Post-surgery ctDNA detection rate was higher in pts with stage III disease compared to stage II (4/12, 33% vs 1/13, 8%). Interestingly, 20% (2/10) pts with stage III disease vs 9% (1/11) with stage II disease had detectable ctDNA after surgery despite favorable surgical findings. Higher pre-treatment ctDNA levels were associated with higher likelihood of ctDNA positivity post-surgery: &lt;1 MTM/mL: 0/4, 0%; 1-10 MTM/mL: 1/9; 11%; &gt;10 MTM/mL: 3/11, 27% (p=0.0025 χ2). ctDNA positivity post-surgery led to change in disease management for two pts. The first pt (inflammatory HR-HER2+ BC), despite achieving pCR, remained ctDNA positive after NAT and surgery, which informed a change in adjuvant treatment. For the second pt (TNBC), ctDNA positivity post-surgery led to detection of radiographically confirmed asymptomatic metastatic relapse and treatment change. Conclusions: ctDNA dynamics during NAT can facilitate real-time assessment of treatment response and can serve as an early indicator of pathologic response, predict ctDNA status after surgery, and inform disease management for BC pts at high risk of recurrence. Clinical trial information: NCT05333874 .

Analytical and clinical validation of a personalized, tumor-informed circulating tumor DNA assay for minimal residual disease detection.

e14545 Background: The detection of minimal residual disease (MRD) through circulating tumor DNA (ctDNA) analysis provides an advanced molecular method for early identification of surgical patients at high risk of recurrence. In this study, we present the development of mClear, a personalized, tumor-informed next-generation sequencing (NGS) assay for MRD detection. Furthermore, we report the analytical and clinical validation processes conducted to evaluate the performance of the MRD assay. Methods: mClear is designed to assess MRD in patients with solid tumors. Whole exome sequencing (WES) was performed on tumor tissues and matched peripheral blood samples to detect somatic variants comprehensively. Personalized MRD assays were carefully designed by selecting up to 40 prioritized variants, including single nucleotide variants (SNVs), small insertions and deletions (InDels), and fusions while ensuring coverage of 21 additional key driver genes. For analytical validation, we utilized a pan-cancer MRD ctDNA quality control product (LDT-999, LDT Bioscience), characterized by known variant allele frequency (VAF) gradients of 0%, 0.005%, 0.05%, and 0.5%, confirmed through droplet digital PCR (ddPCR). We conducted 18 replicate tests at VAF gradients of 0.5% and 0.05%, 23 replicates at the 0.005% VAF gradient, and 16 replicates at the 0% VAF gradient. For clinical validation, preoperative and postoperative blood samples from a cohort of 264 pan-cancer patients were analyzed. ctDNA collected for MRD detection underwent ultra-deep next-generation sequencing (100,000× average depth of coverage). The library preparation process commenced with an input of 30ng DNA. Results: At VAF gradients of 0.5% and 0.05%, the assay achieved an excellent sensitivity of 100%, and at VAF gradients of 0.005% and 0%, it demonstrated a sensitivity of 95.7% and a specificity of 100%. Preoperative ctDNA was detected in 86.7% (72/83) of the pan-cancer patients with 71.4% (5/7), 90.9% (10/11), 85.5% (47/55), and 100.0% (10/10) in pathological stage (pStage)I, pStage II, pStage III, and pStage IV, respectively. In the pan-cancer cohort, the positive rate of longitudinal MRD was 35.7% (75/210) with 17.8% (21/118), 50.0% (13/26), 55.1% (27/49), and 82.4% (14/17) in pStage I, II, III, and IV, respectively. In four patients who relapsed, MRD detection during surveillance preceded radiological recurrence by a lead time of 1-8 months. Conclusions: Our personalized MRD assay demonstrated excellent analytical sensitivity and specificity with a limit of detection (LoD) of 0.005% VAF at the sample level. Furthermore, it displayed high clinical sensitivity for the detection of ctDNA in the pan-cancer cohort, highlighting its potential for monitoring of recurrence.

The impact of adjuvant endocrine therapy (AET) omission in ER-low (1-10%) early-stage breast cancer.

513 Background: Adjuvant endocrine therapy (AET) improves overall survival (OS) in patients (pts) with hormone receptor (HR) positive early-stage breast cancer (BC). For pts with estrogen receptor (ER)-low BC (defined as ER 1-10%), there is controversy regarding AET benefit, given tumor heterogeneity (&gt;40% basal; (1)), and similar chemotherapy response and prognosis to ER-negative (neg) BC. Current guidelines categorize ER-low BC as a separate entity and suggest equipoise regarding AET benefit. We previously determined that AET omission in chemotherapy-treated pts with ER+ BC resulted in a nearly 2-fold increase in death (2). However, the impact of AET omission in patients with ER-low BC is unknown. Methods: Beginning in 2018, the National Cancer Database (NCDB) began to abstract ER as a continuous variable, allowing classification of ER+ tumors as 1-10% or &gt;10%. Therefore, we queried the NCDB 2018-2020 for patients with stage I-III ER+BC treated with neoadjuvant or adjuvant chemotherapy, as these pts have the highest risk of recurrence. ER was assessed as ER-neg (0%), low (1-10%) and ER &gt;10%. OS was analyzed with AET as a time-dependent covariate using Cox proportional hazards regression. Results: 357,085 pts with stage I-III ER+BC were identified, with 10,396 (3%) classified as ER-low. Among pts with ER-low disease, 69% had PR-neg BC and 67% had HER2-neg BC. The majority (77%) were treated with chemotherapy (32% neoadjuvant, 44% adjuvant, 1% unknown timing) and formed our analysis cohort. Among these 7,956 pts, AET was omitted in 3,233 (41%). AET omission was more common for pts with tumors that were PR-neg vs positive (46% vs 30%, p&lt;0.001), HER2-neg vs positive (44% vs 37%, p&lt;0.001), and Ki67≥20% (44% vs 35%, p&lt;0.001). With median follow-up of 3 years, 648 deaths were observed. OS was 94.3% (95% CI: 93.8-94.9%) at 2 years and 87.6% (95% CI: 86.5-88.7%) at 4 years. In unadjusted analysis, omission of AET was associated with worse OS (HR 1.40, 95% CI: 1.19-1.65, p&lt;0.001), with similar effects regardless of PR, HER2, or Ki67 (each interaction test p&gt;0.3). When controlling for age, comorbidity score, year of diagnosis, PR, HER2, and pathologic stage, the adjusted effect of AET omission on OS was HR 1.22 (95% CI: 1.00-1.48, p=0.05). Given assessment of OS was performed during pandemic years, with 1/3 of deaths occurring during the first year of follow-up, we performed a sensitivity analysis to analyze pts who survived to one year after definitive surgery. In this analysis, the adjusted effect of AET omission on OS was 1.24 (95% CI: 1.02-1.51, p=0.03). Conclusions: Omission of AET in pts treated with chemotherapy for ER-low, early-stage BC is associated with significantly worse OS. These data strongly suggest that pts with ER low BC should be counseled regarding the benefit of AET and practice guidelines should recommend AET in this setting. 1. Benefield JNCI 2020. 2. Choong SABCS 2022.

Exploring sexual health in premenopausal patients with hormone positive early breast cancer: Comparison between LHRH and oophorectomy.

e23172 Background: Ovarian function suppression (OFS) is recommended for premenopausal patients with hormone (HR) positive early breast cancer at higher risk of recurrence. This is achieved with the use of the luteinizing hormone–releasing hormone agonist (LHRH) or oophorectomy. Sexual health is an important aspect for women with breast cancer, although unfortunately this issue is often not addressed. The aim of this study was to explore sexual health issues in premenopausal HR-positive patients with LHRH vs. Oophorectomy. Methods: A prospective observational study was conducted during the period of June 2023 and December 2023, enrolling premenopausal patients with Early stage HR positive (HER2 positive or negative) breast cancer diagnosed between 2017 and 2023, who were treated with OFS and remained free of disease. Involved patients were divided in two groups: Group A – received LHRH and Groups B - underwent oophorectomy. All patients were surveyed with EORTC QLQ-BR-45 questionnaire during their follow-up or scheduled LHRH injection visits at clinic. The questionnaire included Functional (F) and Symptom (S) scales evaluating sexual functioning, sexual enjoyment, endocrine therapy symptoms, endocrine sexual symptoms. Results: It was planned to enroll 100 patients in the study, but only 34 patients (24 in Group A, 10 in Group B) consented to participate, the majority of patients did not want to share their sexual life issues, even anonymously. Of those enrolled, median age was similar (42 in group A, 43 in group B), all had stage I-II breast cancer, and all were in continued remission at the time of enrollment. A similar proportion had HER2 positive disease (25% and 20%, respectively). Far more people in Group A were treated with breast conserving surgery (67% vs 30%, respectively) with 20% of participants in in Group B undergoing bilateral mastectomy. More volunteers received chemotherapy in Group A (88% vs 60% in group B). Among those in Group B, 6 of 10 were previously treated with LHRH before oophorectomy and the procedure was done due to endometrial hyperplasia (n = 3), known BRCA mutation (n = 1), persistent estrogen levels despite LHRH (n = 1), and patient preference (n = 5). More patients had a partner at enrollment in group B (90% vs 67% in Group A); only one person identified as a lesbian (enrolled in group B). F score S &gt; 60 was noted in more Group A vs Group B participants (50% vs 30%). More people in Group A had S score S &lt; 40, indicating higher quality of life (79% vs 50%, respectively). Conclusions: The study suggests that sexuality after cancer is a difficult area to study in Georgia, likely due to cultural issues. While we could not account for the contribution of known variables that impact sexuality in this population (e.g. surgery type, chemotherapy) due to small numbers, our data suggest that LHRH antagonist use may have a lesser risk to sexual function compared to oophorectomy.

Cryptolepine: A naturally derived alkaloid inhibits breast cancer progression by blocking cell cycle progression and inducing apoptosis.

e13151 Background: Triple Negative Breast cancer is an aggressive breast cancer subtype. TNBC has a more aggressive clinical course, an earlier age of beginning, a larger propensity for metastasis, and worse clinical outcomes as evidenced by a higher risk of recurrence and a shorter survival rate when compared to hormone receptor-positive or HER2-positive illness. Currently, the primary options for TNBC treatment are surgery, radiation, and chemotherapy. These treatments, however, remain ineffective due to recurrence. However, given that p53 mutations have been identified in more than 60–88% of TNBC, translating p53 into the clinical situation is particularly important in TNBC. Given the scope that some natural drugs can be used as specifically targeting prospective therapeutic in TNBC and to sensitize this aggressive malignancy while reducing side effects. In this study, we screened and evaluated the therapeutic potential of CRP in TNBC in-vitro models being an anti-malarial drug it could be repurposed as an anti-cancer therapeutic in TNBC. Moreover, the cytotoxicity activity of cryptolepine to TNBC cells and a detailed anti-tumor mechanism in mutant P53 has not been reported. Methods: MTT assays were used to examine the cytotoxicity and cell viability activity of Cryptolepine in TNBC, non-TNBC T47D and MCF-7 and non-malignant MCF10A cells. Scratch wound and clonogenic assay was used to evaluate cryptolepine’s effect on migration and colony forming ability of TNBC cells. Flow cytometry, MMP and DAPI was used to assess cell cycle arrest and cell apoptosis. The expression of proteins was detected by western blots. The differential expression of RNAs was evaluated by RT-PCR and the interaction between P53 and drug was evaluated computationally using in-silico approach and in-vitro using ChIP assay. Results: In this study, we found that cryptolepine has more preferential cytotoxicity in TNBC than non-TNBC cells. Notably, our studies revealed the mechanism that cryptolepine can induce intrinsic apoptosis and inhibit migration, colony formation ability, induce cell cycle arrest by inducing conformational change in the mutant P53 thereby increasing its DNA binding ability and also inducing its own transcriptional activation to synthesize new P53 protein and hence activating its tumor suppressing potential significantly. Conclusions: Our study revealed that CRP significantly reduced the proliferation, migration and colony forming ability of TNBC cells lines. Moreover, it was revealed that CRP induces cell cycle arrest and apoptosis by activating mutant P53 and enhancing its DNA binding ability to induce its tumor suppressing ability.