Percentage Of Pts Research Articles

Reduced blood product utilization via implementation of an anemia clinic and consult service in a large health system hospital.

e18716 Background: An Anemia Clinic program was started Sept. 2016 as part of system wide implementation of Patient Blood Management (PBM) initiated in 2015. Methods: The Anemia Clinic accepted referrals for non-cancer anemia, predominantly preoperative cardiovascular surgery (CVS) Pts. Hgb thresholds were < 13 g/dL in men and < 12 g/dL in women. Non-anemia cytopenias triggered Hematology referral. All Pts were screened for iron, B12, folate, and reticulocyte count. Nutrient deficiencies were supplemented. Pts with CKD or chronic disease were considered for erythropoiesis stimulating agents. Results: PBM implementation resulted in a drop in packed red blood cell (PRBC) usage (Table). Of CVS Pts pre-operatively anemic in 2022, 211 were referred to the Anemia Clinic and 373 were not. The percentage of Pts who received PRBCs after Anemia Clinic referral was not statistically different from those who were not referred (61.1% vs. 54.2% chi-square p = 0.10). Of preoperatively anemic Pts who were transfused in 2022, an average of 2.41 PRBCs were used in the referred group vs. an average of 2.21 PRBCs in those in the not referred group (negative binomial p = 0.25). Length of stay (LOS) which was a median 10d ( P25= 6d, P75 =17d) in the referred group vs a median 10d ( P25= 7d, P75 =17d) in the non-referred group was not statistically different between groups (Kolmogorov-Smirnov p = 0.84). LOS analyses of observed-to-expected (O/E) ratios used the Premier Healthcare Providers Alliance Database (PHD) which contains data on approximately 45% of US hospital discharges. For 2022 through Nov. the referred group had an O/E = 0.93 (observed LOS μgeo = 10.51 days, expected LOS μgeo = 11.32 days, N = 183). The not referred group had an O/E = 1.10 (observed LOS μgeo = 10.44 days, expected LOS μgeo = 9.50 days, N = 321). Conclusions: PBM decreased PRBC use through systematization of best practices during the initial year, and that decrease has persisted for seven years. Subsequent addition of Anemia Clinic services did not decrease PRBC use further. A trend toward shorter LOS for patients referred to Anemia Clinic was not observed this year, but the difference in LOS from the not referred group is not statistically significant and observed LOS for the referred group was lower than expected LOS. Our methods improved nutrient deficiency identification which may improve both later health outcomes not detected here and access to treatment for hematologic malignancies. [Table: see text]

Therapy preferences of patients with cancer.

e24205 Background: Clear understanding of patient (pt) preferences is crucial for creating a treatment (tx) plan that aligns with pt's goals and expectations. We developed "Therapy Preference Scale" (TPS), a self-reported questionnaire, to measure tx preferences of pts with cancer. TPS includes 30 questions: 19 questions on pt preferences on safety, efficacy, and other aspects of therapy (on scale of 0-10), 8 questions on importance of different aspects of tx (on 4-item Likert scale with choices of 'strongly disagree,' 'disagree,' 'agree,' and 'strongly agree.'), and 3 questions on intent of therapy, expenses, and life expectancy gain. This report presents results of the 8 questions rated on the 4-item Likert scale from a prospective study using TPS. Methods: 300 pts > 18 yrs with a cancer diagnosis completed TPS. We divided pts into 4 groups: Male < 60 yrs (M < 60), Male ≥60 yrs (M ≥60), Female < 60 yrs (F < 60), and Female ≥60 yrs (F ≥60). We compared responses between M < 60 and M≥60 and between F < 60 and F≥60. The responses were categorized into 2 groups: "disagree" (combining "strongly disagree" and "disagree") and "agree" (combining "strongly agree" and "agree"). Results: Median age was 61 yrs (range 19-89). 62% had solid tumors. 57% indicated cure as their tx goal versus gain in life expectancy without cure (35%) or symptom relief (8%). 4 groups were 20% M < 60, 32% M ≥60, 19% F < 60, and 29% F ≥60. M < 60 were more likely to accept tx with side effects and financial burden, while M ≥60 prioritized avoiding poor quality of life (QoL). F < 60 were more likely to undergo tx causing significant pain, while F ≥60 would avoid permanent cognitive impairment. Table 1 shows percentage of pts who agreed with the 8 questions. Conclusions: Despite similar preferences for a cure, age and gender play role in prioritizing tx options, including those with potential side effects such as life-threatening infection, poor QoL, financial burden, severe pain, and permanent cognitive impairment. TPS can improve the precision medicine approach and aid in choosing the right tx for each pt. [Table: see text]

Circulating tumor DNA (ctDNA) dynamics in response to checkpoint inhibitor immunotherapy in colorectal cancer.

e15540 Background: Circulating tumor DNA (ctDNA) is emerging as a sensitive and specific non-invasive marker of active disease in patients (pts) with colorectal cancer (CRC) and may be used for monitoring response to immunotherapy (IO) in all solid tumors. However, the dynamics of ctDNA changes in response to IO and their correlation to radiographic response has not been well-established. Methods: We searched for all pts in our institution who received IO for a solid tumor diagnosis and who also received quantitative ctDNA testing using Signatera. We retrospectively evaluated radiographic treatment response using RECIST v1.1 and correlated radiographic response to time-matched changes in quantitative ctDNA. Objective response rate (ORR) was defined as the percentage of pts achieving radiographic partial response (PR) plus complete response (CR). Results: We identified 6 pts with advanced CRC who underwent serial ctDNA testing while receiving IO; all patients had loss of mismatch repair protein expressions. Median age was 70 years (range 35-90), and 50% of patients were female. All pts were actively receiving IO at the time of data cutoff. Two pts were receiving ipilimumab plus nivolumab, the other 4 pts were receiving pembrolizumab; 1 pt had only received 1 cycle of IO at time of cutoff, thus did not have on-treatment imaging and was excluded from further analysis. For the response evaluable patients, ORR was 100%, with all pts (5/5) achieving PR after median of 3 cycles (range 1-3 cycles) of treatment. Quantitative ctDNA decreased by 83-100% in all pts analyzed. 1 pt had radiographic (pseudo-)progression at time of first radiographic assessment, however at this timepoint, ctDNA had decreased by 60%; this pt continued on immunotherapy based on clinical benefit including ctDNA data. Subsequent radiographic assessment of this pt confirmed partial response and ctDNA response decreased by total of 95% after a total of 3 cycles of IO. Conclusions: In this small patient population, we show that quantitative ctDNA directly corresponds to radiographic response to IO, and may guide treatment decisions by differentiating pseudoprogression from true progression. Further longitudinal studies will show if ctDNA changes correlate to duration of response, early identification of treatment resistance, and ultimately survival.

Belantamab mafodotin (belamaf) for relapsed/refractory multiple myeloma (RRMM): A real-world observational study update.

e20046 Background: A prior retrospective analysis of US patients (pts) with RRMM suggested that pts treated with belamaf, a BCMA-targeting antibody-drug conjugate, experienced similar outcomes to those who received belamaf in the pivotal DREAMM-2 study. This updated analysis aimed to characterize pts, assess occurrence and management of ocular adverse events (AEs), and evaluate belamaf effectiveness in a real-world setting. Methods: This retrospective, longitudinal, observational study used data sourced from the US EHR-derived Flatiron Health de-identified database (01/01/2011–06/30/2022). Eligible pts had a confirmed MM diagnosis, initiated belamaf after FDA approval (08/05/2020; first administration=index date), were ≥18 years old at index, and had chart abstraction data for ocular safety and treatment effectiveness. Data on ocular AEs were reported separately for all pts and pts with ≥4 months (mo) of follow-up to allow for sufficient follow-up to evaluate incidence of ocular AEs and their mitigations. Tumor response was assessed in all pts, along with Kaplan-Meier estimates of duration of response (DoR), overall survival (OS), and progression-free survival (PFS). Results: Of the 184 pts included in the study, mean age was 68.7 years; 64% were White and 47% were female. Eastern Cooperative Oncology Group (ECOG) status was ≥2 in 28% patients, 62% had received ≥5 prior lines of therapy, and 82% were triple-class refractory. Median (IQR) follow-up was 4.1 (1.9–8.5) mo. Among pts with ≥4 months of follow-up (n=94) 75% had ≥1 ocular AE, with keratopathy and blurred vision being the most frequent. Mean (SD) time to first ocular AE was 39 (34) days. Most ocular AEs were managed by therapy hold (69%; of which 73% restarted belamaf) and/or AE treatment (63%). The median dose hold due to ocular AEs was 43 days (physician-reported keratopathy: mild, 21 days; moderate/severe, 56 days). In all pts, 39 (21%) had a derived tumor response based on serum free light chain levels, (partial response: 74%, very good partial response: 51%). For all pts, the estimated median DoR was 9.1 mo, PFS 4.5 mo, and OS 7.9 mo, while the 6-month DoR rate was 57%, PFS rate was 46%, and OS rate was 58%. Conclusions: Overall, belamaf was effective in the real world setting in heavily pre-treated pts with RRMM and limited therapy options. The AE profile was consistent with DREAMM-2. Ocular AEs were manageable and despite their occurrence, a high percentage of pts remained on treatment, suggesting belamaf may fill an unmet need for triple-class refractory pts with RRMM. [Table: see text]

Rose geranium in sesame oil nasal spray to improve symptoms of nasal vestibulitis: A phase III double blinded randomized controlled trial.

12114 Background: A retrospective study suggested a potential benefit from rose geranium in sesame oil nasal spray for alleviating nasal vestibulitis symptoms in patients (pts) undergoing chemotherapy. Methods: Pts undergoing active chemotherapy who reported moderate or worse nasal symptoms were randomized 1:1 to receive a rose geranium in sesame oil nasal spray (RG) or an isotonic saline nasal spray (IS), administered twice daily for two weeks. Consenting pts completed nasal symptom questionnaires at baseline and then weekly while on treatment. The number and percentage of pts experiencing improvements in their nasal symptoms 2 weeks after initiating the nasal spray, defined as symptoms moderately (2) or very much (3) better on a 7-point global impression of change score (ranging from scores of -3: very much worse, to 3: very much better), was estimated within and then between each randomized arm, using Fisher’s exact test (5% significance level). The estimated odds ratio was determined (95% confidence interval). After 2 weeks, pts initially randomized to IS were allowed to cross-over to RG and completed weekly surveys. Results: 106 pts consented to this study; 43 pts in the RG arm and 41 in the IS arm were evaluable for the primary endpoint. Pts had a mean age of 57.8 (SD 13.9). Demographic characteristics and baseline nasal symptoms were similar between arms. The most prominent baseline nasal symptoms were dryness (36%) and bleeding (35%). Of the 43 evaluable pts who received RG, 67.4% reported improved nasal symptoms, compared with 36.6% of the 41 pts who received IS (p=0.009; Table). On the global impression of change score, pts who received RG had a mean score of 1.93 (SD 1.16), compared to a mean score of 0.98 (SD 1.41) among pts who received IS. Adjusting for potential confounding factors, pts who received RG had a 4.56 odds of responding to the nasal spray, compared with those who received IS (p=0.005). There were no significant differences between pt responses based upon type of nasal symptoms, age, allergies, or gender. Adverse events were sparse and did not differ between arms. 34 pts crossed over to RG after week 2. Among the 29 pts who completed final surveys, 37% reported a response on IS, 79% reported a response on RG. Conclusions: Rose geranium in sesame oil nasal spray significantly improves nasal vestibulitis symptoms among patients undergoing chemotherapy. Clinical trial information: NCT04620369 . [Table: see text]

Racial disparity in the clinical outcomes of HER2-low and HER2-zero early-stage breast cancer.

e12602 Background: The expansion of the spectrum of HER2 breast cancer (BC) to include HER2-low status has had major impact in oncology. More than half of the BC patients (pts) are now categorized as HER2-low. With the recent approval of antibody-drug conjugates in HER2-low BC, HER2-low has emerged as a distinct targetable entity. BC pts who attain pCR after neoadjuvant chemotherapy (NAC) have a better prognosis. We analyzed the association of race with attainment of pCR among HER2-low and HER2-zero pts treated with NAC and with survival. Methods: We queried the National Cancer Database for stage I, II, III BC pts who received NAC from 2010 – 2019. The population was divided into two cohorts: HER2-low and HER2-zero. All associations were compared using Kruskal-Wallis, Pearson’s Chi-Squared, and Fisher’s Exact Tests. Multivariate cox regression models were generated for overall survival (OS) adjusted for age, race, stage, grade, body mass index, treatments, subtypes, insurance and comorbidities. Results: A total of 72,279 pts was included in the analysis (HER2-zero = 71,091, HER2-low = 1,188). There was higher hormone receptor (HR)-positivity in HER2-low vs. HER2-zero groups (69% vs 54%, p < 0.001). Higher percentage of pts had private insurance in the HER2- low group (60% vs 4%, p < 0.001). Race, age, clinical T and N-staging were distributed equally between both cohorts. Among all races, those with HER2-low status had lower pCR compared to HER2-zero, but this was not statistically significant. The rate of pCR was similar across racial groups in both HER2-low and HER2-zero groups, though was not statistically significant. In the HER2-zero group, Blacks had worse while Asians had better survival compared to Caucasians in overall (Blacks: hazard ratio (HR) 1.36, 95% CI = 1.3-1.4; Asians: HR 0.60, 95% CI = 0.57-0.74), HR-positive (Blacks: HR 1.4, 95% CI = 1.3-1.4; Asians: HR 0.60, 95% CI = 0.53-0.75) and HR-negative (Blacks: HR 1.2, 95% CI = 1.17-1.29; Asians: HR 0.69, 95% CI = 0.58-0.83) subtypes (all p < 0.001). However, this racial disparity in survival was not observed in the HER2-low group in the overall population (Blacks: HR 1.1, 95% CI = 0.7-1.5, p = 0.5; Asians: HR 0.38, 95% CI = 0.14-1.03, p = 0.06) or within subtypes. Interestingly, among Blacks, pts with HER2-zero disease had worse survival compared to HER2-low disease (5-yr OS: 73% vs 81%, p = 0.02, HR 1.4, 95% CI = 1.05-1.9, p = 0.02). This survival difference was not observed in any other races. Conclusions: Racial disparity in survival plays a role in the HER2-zero, not in HER2-low early-stage BC. Blacks who received NAC have decreased OS in the HER2-zero group, not in HER2-low group compared to other races. More studies are needed to confirm this finding and identify the mechanism underlying this disparity. Among Blacks, those with HER2-zero BC had worse survival compared to HER2-low. This highlights the need for personalized treatment options for Blacks for HER2-zero BC.

Dosing patterns and treatment patterns in real-world patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who received FOLFIRINOX in the first line.

e16255 Background: While FOLFIRINOX (FFX) demonstrated a significant overall and progression-free survival benefit vs. gemcitabine in the PRODIGE 4/ACCORD 11 trial among previously untreated patients (pts) with metastatic pancreatic ductal adenocarcinoma (mPDAC), treatment with FFX was associated with a higher rate of grade 3/4 adverse events (AEs). In an effort to reduce toxicity, modified FFX (mFFX) regimens that employ lower doses of components of the regimen have been developed. To better understand the frequency and degree of dose modifications in practice, we examined real-world (RW) dosing patterns among mPDAC pts receiving FFX in first line (1L). Methods: This retrospective observational study utilized the Ontada Clinical Data View: Pancreatic Cancer database. Adult pts diagnosed with mPDAC between January 2015 and November 2022 who initiated treatment with FFX or mFFX within 90 days of their diagnosis for metastatic disease (1L) were included in the study. Pts were required to have an available body surface area measurement within 7 days of the index date. Doses of each FFX component were measured during cycles in which pts received all four components of the FFX regimen on the same date. mFFX was defined as administration of < 150mg/m2 of irinotecan or < 2,720mg/m2 5-FU total during cycle 1. Results: Of the 1,326 pts eligible meeting inclusion criteria and receiving 1L treatment with FFX or mFFX, 1,325 received mFFX and 1 received FFX. The median age at 1L initiation was 65yr (IQR: 58–70), 57% (754 pts) were male, 69% (916 pts) were white, 15% (197 pts) had an ECOG score of 0, 42% (550 pts) had an ECOG score of 1, and 78% (1028 pts) were stage IV at diagnosis. The bolus of 5-FU was frequently omitted—only 20% (262 pts) received it in the first cycle. If pts received the bolus, they did not receive the 5-FU infusion, with the exception of 1 pt. For pts receiving at least two cycles, the percentage of pts with dose reductions of ≥10% (≥20%) between the first and last cycle were 20% (11%) for the 5-FU infusion, 18% (13%) for the 5-FU bolus, 34% (21%) for irinotecan, 12% (9%) for leucovorin, and 40% (28%) for oxaliplatin. Median starting doses were 2400, 401, 152, 399, and 85 mg/m2 for the 5-FU infusion, bolus 5-FU, irinotecan, leucovorin, and oxaliplatin components, respectively. The median number of cycles was 5 (IQR: 3–10) and the median dose intensity per week was 940 mg/m2 for 5-FU, 179 mg/m2 for leucovorin, 38 mg/m2 for oxaliplatin, and 73 mg/m2 for irinotecan. Conclusions: In a RW cohort of pts with mPDAC treated with 1L FFX, almost all received a modified version of the regimen. The 5-FU bolus was omitted for most pts. Doses of other components fell over time for a notable percentage of patients, which may reflect clinician efforts to manage FFX toxicity.

Early ctDNA reduction may identify patients with stable disease and long OS on tebentafusp.

9589 Background: Tebentafusp, a bispecific (gp100 × CD3) ImmTAC showed significant overall survival (OS) benefit (HR 0.51) versus investigator’s choice in a Phase (Ph) 3 trial in first line (1L) HLA-A*02:01+ adult patients (pts) with metastatic uveal melanoma (mUM) [Nathan NEJM 2021]. In Ph2 and Ph3 trials of tebentafusp, OS was improved regardless of RECIST best response and the degree of early reduction in ctDNA was a better predictor of OS [Carvajal Nat Med 2022; Sullivan AACR 2023]. Here we explored whether early on-treatment reduction in ctDNA could distinguish pts with stable disease (SD) and long OS vs those with SD and short OS in a Ph3 trial of tebentafusp in 1L mUM pts. Methods: 1L HLA-A*02:01+ pts with mUM received 68 mcg tebentafusp weekly intravenously after intra-patient dose escalation (NCT03070392). Response was assessed by investigators per RECISTv1.1. Sera collected at baseline (BL) and week 9 on tebentafusp were analyzed for ctDNA using targeted mPCR-NGS assay for mutations in 15 genes including GNAQ, GNA11, SF3B1, CYSLTR2, PLCB4 and EIF1AX. Landmark OS from week 9 was analyzed in subsets with ≥0-3 log reductions in mean tumor molecules (MTM) per ml of serum on treatment. Data cutoff 11-Nov-2022. Results: 76/245 (36%) tebentafusp-treated pts had best response of SD, with a median OS of 29 months and were evaluable for ctDNA. Baseline tumor burden as assessed by sum of longest lesion diameters and percentage of pts with elevated BL serum LDH were greater in the subset with < 1 year (yr) OS (median 70 mm and 64%, respectively) than in subsets with OS ≥ 1 yr (median 42 mm, 11%) or OS ≥ 2 yrs (median 31 mm, 9%). Almost half (36/76; 47%) of all SD pts had detectable ctDNA mutations in one or more UM genes at baseline. Baseline ctDNA levels were similar across survival groups. By week 9 on-treatment, ctDNA reduction was observed in 34/36 (94%) evaluable SD pts, including 29/36 (81%) with ≥ 0.5 log reduction, 18/36 (50%) with ≥ 2 log reduction and 16/36 (44%) with undetectable ctDNA (clearance). Deeper reductions in ctDNA were associated with better OS (Table). Conclusions: In this Ph3 trial, ctDNA reduction by week 9 on tebentafusp was strongly associated with improved OS in pts with best RECIST SD. Early ctDNA reduction may predict SD patients with long OS on tebentafusp. [Table: see text]

Effect of the large waves of COVID-19 on false-positive results in annual lung cancer screening.

e18596 Background: Chest X ray (CXR) has been the most common screen test procedure for detection of lung cancer. We have shown that repeat visitors (R) had a significantly lower proportion of CXR abnormalities requiring medication than the first-time visitors (F) at annual lung cancer screening. (Kimura T. Health Prim Car, 2021). In 2022, Japan experienced three large waves of COVID-19 mainly the Omicron variants (the 6th: Jan-Mar, the 7th: Jul-Sep and the 8th: Oct to present). The later the wave, the larger the scale. The Omicron variant spreads more easily than the original or the Delta variants up to the 5th waves. The hypothesis was that these COVID waves may have influenced lung cancer screening. Methods: Our clinic “MedCity21” is a university outpatient clinic for a complete medical check-up as part of a private health screening program. Of course, we check temperature, respiratory symptoms, and any history of COVID infection and vaccination of the participants (pts). Our facility allows COVID-infected pts to have medical check-ups four weeks after they are cured. The pts with abnormalities detected on CXR were notified by telephone request and invited to our specialty clinic for chest CT scan as further examination. Each year from 2018 to 2022, we examined the varieties of abnormal shadows on CXR and CT scans and compared the differences between 2022 and each year before to 2022 using the chi-squared tests. Results: In 2022, there were 14522 pts of which F and R were 27.1% and 72.9% respectively. The percentage of pts with a history of COVID was 1.68% in January, but gradually increased, reaching a plateau of 20% in October. There were 231pts (1.6%) with CXR abnormalities requiring further investigation. The rates in F and R were 1.3% and 1.7%, respectively. A total of 132 pts (56.7%) of 63 pts in F and 69 pts in R underwent chest CT scans at our facility after the call for recommendation for further investigation. The distribution of CXR and CT variations was consistent with our previous report. There was one confirmed case of lung cancer among F, and 2 among R in 2022. It should be noted that the CT confirmation revealed that there were 10 pts with nodular shadow on CXR, of whom 5 were found to have COVID infection after 1 month follow-up. Conclusions: There was a significant decrease in the number of first-time visitors in 2022 compared to previous years (p < 0.001). The percentage of cases returning to our clinic for CT for further investigation has decreased dramatically (p < 0.001). These were attributed to the large COVID waves. Notably, for the first time in the last 5 years, the detection rates of CXR abnormalities were reversed for R and F. In some cases, nodule shadows were difficult to determine whether they were lung cancer or COVID. The number of people with previous COVID-19 infection will continue to increase. The COVID pandemic and subsequent behavioral changes have affected the way people manage their health status.

The evolution of treatment patterns in patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC) and clinical outcomes: Results of a longitudinal observational cohort study in England.

e16559 Background: Treatment (tx) guidelines for pts with la/mUC in England have evolved over the last decade following the approval of successive immune checkpoint inhibitors (ICIs). However, the impact of this evolution on routine clinical practice (RCP) remains unclear. We aimed to describe shifts in tx patterns and associated clinical outcomes in RCP in England. Methods: This retrospective cohort study included pts aged ≥18 years, with primary stage III/IV UC diagnosis (dx) between Jan 1, 2013 and Dec 31, 2020, in the National Cancer Registration Dataset with follow-up to May 31, 2022. Pts’ dx were stratified at Dec 31, 2017, to split the cohort into pre- and post-ICI eras. Lines of systemic therapy were derived via an algorithm using data from the Systemic Anti-Cancer Therapy dataset. Summary statistics and overall survival (OS) were calculated and compared using χ2 and log-rank tests, respectively. The Kaplan-Meier method was used to estimate median OS from dx and from systemic tx initiation. Results: In the pre- and post-ICI groups, the majority of pts were male (65.7% and 65.5%) and mean modified Charlson-Deyo Comorbidity Index was 3.4 and 3.5, respectively. Mean age was 73.2 years in both groups, while a higher percentage of pts in pre-ICI era had stage IV disease at dx (68.3% and 50.0%; p<0.001). The rate of first line (1L) tx increased from 30.4% to 35.3% (p<0.001) and second line (2L) from 31.2% to 37.3% (p<0.001). The proportion of pts who received ICI in any line increased from 13.7% to 31.6% (p<0.001). Median OS from 1L tx improved from 13.8 to 15.5 mo. Conclusions: While pt demographics did not change considerably between the two groups, 1L and 2L tx rates moderately increased over time, although remained below 40%. In both groups, >85% of treated pts received 1L platinum chemotherapy, consistent with guidelines. In the post-ICI era, approximately one-third of treated pts received ICI therapy in any line. Improved OS from 1L tx could be partially attributable to the increased availability and uptake of ICIs. [Table: see text]

Does the severity of the course of COVID-19 in pts without hospitalization and no history of cardiovascular disease affect of cardiac arrhythmias

Abstract Funding Acknowledgements Type of funding sources: None. Background Many studies have shown that arrhythmias are an independent risk factor for death and the course of COVID-19 in these pts. However, there are no data on the impact of the SARS CoV-2 virus on pts with a domestic course of COVID-19 without a previous history of cardiovascular disease. The aim of the study was to assess whether the severity of the home course of COVID-19 has an impact on cardiac arrhythmias in pts without previous cardiovascular disease. Methods The study included only pts after COVID-19 without hospitalization, without previous cardiovascular disease. Pts were divided into two groups depending on the severity of the COVID-19 course: Gr 1 with severe course of disease: symptoms lasting 7, dyspnoea lasting with oxygen saturation below 94 lasting more than 3 days and Gr 2 – pts with mild course of COVID-19 who do not who did not meet the eligibility criteria for Group 1. In pts, in the post-COVID period (mean 12±6 weeks an standard 12-lead ECG (ECG) and 24-h Holter ECG (Holter) were performed. Following parameters were analysed in ECG: mean heart rate (mHR); PQ interval (PQ), QRS duration (QRSd); corrected QT interval (QTc); atrial fibrillation (AF); inappropriate sinus tachycardia (ITS), QRS duration > 120ms (QRS>120); LBBB, RBBB, QRS fragmentation (QRSf); STT wave abnormalities (STTabn); presence of premature supraventricular (SVES) and ventricular (VES) complexes; in 24-h Holter ECG: sinus tachycardia (STach), new atrial fibrillation (AFHolter), SVES > 1000/24h (SVES>1000); supraventricular tachycardia (TSV), VES > 1000/24h (VES>1000), Couplet VES (VEScouplet), non-sustained sustained tachycardia (nsVT); ventricular tachycardia (VT), block A-V 2nd typ 2 and/or block A-V 3rd grade (AVdist). Next, all above parameters were compared between both groups. Results A total of 1032 patients, (64% women and 36% men), mean age was 47.8± 16.5 were included in the analysis., of whom 336 pts (32,5%) had severe course of COVID-19. There was no significant differences in all except the number of nsVT which were significant more frequent in pts with severe course of COVID-19. (Gr 1 0,056 ±0,482 vs Gr 2=0,007±0,085; p=0,024). In no one pts VT and or VF was found. Results regarding number of pts in both groups and ecg abnormalities and cardiac arrhythmias are summarized in Table 1. Multivariate regression analysis showed that age (RR 1.012, 95%CL 1.002-1.024 p=0,02) and nsVT (RR 3,328 95%CL 1.057-10.481 p=0,039) are significantly related to severe course of non hospitalised COVID-19 pts. Conclusions Atrial Fibrillation and nsVT episodes occurred significant more frequent in non hospitalised pts with COVID-19 without history of cardiovascular disease in severe course of disease but in small percentage of pts. Age and episodes of nsVT are significantly related to the severity of COVID-19 in non hospitalised pts with no history of cardiovascular disease.

Chronotropism in CPET - Is incompetence limiting functional capacity?

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Chronotropic incompetence (CI) is defined as the inability to reach 80% of the expected reserve frequency for age during exertion, and it is frequently observed in stress tests of patients undergoing cardiac rehabilitation programs due to a combination of factors, that include the use of betablockers. Despite the theoretical basis for suggesting that a lower peak heart rate is related to a lower tolerance to exertion, we lack data correlating the CI to the maximal functional capacity, measured in cardiopulmonary tests as the maximal oxygen volume consumption (peak VO2). Purpose To correlate the impact of CI on functional capacity in patients (pts) undergoing a cardiac rehabilitation program and try to find the best value of chronotropic incompetence that could predict a worse prognosis. Methods Prospective cohort study which included consecutive pts who were submitted to cardiopulmonary exercise test (CPET) during 5 years in a tertiary hospital. Demographic data were analyzed and medication with beta blocker was registered. CI and chronotropic index were calculated using the equation (220-age) for estimating maximum HR. ROC curve method and Kaplan-Meier survival analysis were used to evaluate the cut-off efficacy. Results We analyzed 358 CPET and 74,1% patients (n=206) were under beta blocker therapy (7,6% high dose). The majority of the patients had CI (83.5%); CI was more frequent in pts under BB therapy although it didn’t reach statistical significance (p=0.12). A low maximum predicted heart rate (mpHR) was associated with low peak VO2 (p=0.02) and a mpHR < 61% was the best value to predict peak VO2< 12mL/(kg.min) (AUC=0.746, S=72; E=65), despite not showing association with cardiovascular events. Regarding the chronotropism, 96.9% of the pts were categorized as having a low chronotropic index . A CI < 0.38 was the best cut-off to predict a peak VO2<12 mL/(kg.min) (AUC=0.81, S=72, E 76) and it was predictor of all-cause hospitalizations (p=0.015). Conclusion This study shows a high percentage of pts with CI. A low cronotropic index was associatated with low peak VO2 and was a predictor of all-cause hospitalizations.

C68 PREVALENCE OF CARDIOINHIBITORY SYNCOPE IN A SERIES OF PATIENTS WITH THE CORRECT TILT TABLE TEST INDICATION. PRE–TEST PREDISPOSING FACTORS IDENTIFIED

Abstract Purpose of study : Data from the last ESC LLGGs on syncope show that the prevalence of cardioinhibitory syncope ( IIB according to VASIS classification ) at the Tilt table test (TTT) is 8% in the general population and 13% in patients with positive TTT ( TTT + ).The purpose of our work was to evaluate a) the prevalence of TTT+ with cardioinhibitory response (IIB VASIS) in a population correctly subjected to TTT for suspected neuromediated reflex syncope; b) if there are predisposing pre–test indicators; c) how many patients (pts) with TTT + with IIB response suitable for permanent pacemaker implant (PPM ) Material and methods : In our laboratory, in the last 6 years, there have been considered 989 patients for suspected neurally reflex syncope (NMRS) and subjected with correct indication to TTT using the Italian protocol. From this population was extrapolated a case study of pt with TTT+ for vasovagal syncope. In this case the prevailing TTT+ with IIB VASIS response was evaluated. Were sought multivariate analysis indicators pre test predisposing. In addiction, it was evaluated how many pts there was a correct indication for a PPM. Results TTT+ occurred in 641 pts ( 64.8%). In this case the TTT+ was found in 79 % of the pts with suspected typical NMRS and 55 % of the pts with suspected atypical NMRS. In 641 pts with TTT+ the prevalence of IIB response was observed in 41.1 %. In particular in 59 % of pts with typical NMRS and 29 % of pts with atypical NMRS ( p 0.0001 ). Multivariate analysis was identified as indicators independently associated with the IIB response male ( HR 0.5981 p .0134 ), syncope with trauma ( HR 3.1123 p .0015 ), hypertensive heart disease ( HR 2.9834 p.0058 ). The TTT+ IIB pts that had a correct indication to the PPM implant according to ESC LLGGs were 21 % ( 134 pcs ) Conclusions the prevalence of cardioinhibitory syncope in our case studies is reused higher (41 %) than the literature data in previous cohorts ( 13–16 %). The percentage of pts with correct indication at PPM was almost 1 in 4 ( 21%). Trauma and hypertensive heart disease appear to be independent factors of cardioinhibitory TTT response useful to guide therapeutic diagnostic conduct.

Abstract PD1-04: Neighborhood Deprivation Index and Survival in Breast Cancer in the United States

Abstract Introduction: Socioeconomic status (SES) of the individual and neighborhood plays an important role in patients’ (pts) access to the health system and eventually in the outcomes of their disease. Owing to the inequalities in opportunities, education, income, and developmental infrastructures, the area with deprived individual and neighborhood SES may be associated with a poor prognosis of certain malignancies and worse outcomes. We analyzed the association between Neighborhood Deprivation Index (NDI) and survival of early-stage breast cancer (BC). Methods: The NDI created by the National Cancer Institute includes variables from dimensions, such as, wealth and income, education, occupation, and housing conditions which have been used for our analysis. We analyzed the impact of NDI in quintiles (qn). We queried the SEER database from 2010-2016 for all early-stage BC pts and studied the overall survival (OS) and disease-specific survival (DSS) of BC in association with NDI. Cox multivariate regression modeling was performed to measure the association between NDI and OS/DSS. Kruskal-Wallis test was used for comparison for continuous and Chi-Square test was used for categorical variables. All analyses were adjusted for age, race, grade, insurance, surgery (SX), radiation (RN), and chemotherapy (CT). Statistics were performed using SAS. Results: Out of the 88,572 early-stage BC pts, 27.4 % (n= 24,307) were in the most deprivation (MD) qn, 26.5% (n= 23,447) were in the average deprivation (AD) qn, 17% (n= 15,035) were in the above average deprivation (AA) qn, 15.6% (n= 13,838) were in the least deprivation (LD) qn and 13.5% (n= 11,945) were in the below average deprivation (BA) qn. The median age of pts in the LD qn was 59 and MD qn was 61 yrs, p< 0.001. There was a predominance of racial minorities in the MD and AA qn with Blacks being 13-15% and Hispanics being 15% compared to only 8% Blacks and 6% Hispanics in the LD qn (p< 0.001). There was a higher percentage of uninsured pts in the MD qn compared to LD qn (2.2% vs 1.7%, p< 0.001). There were more rural areas in MD qn compared to LD qn (25.9% vs only 0.7%, p< 0.001). There were more pts with grade III disease in MD qn compared to LD qn (34% vs 31.9%, p< 0.001). 96.1% pts underwent SX in MD qn vs 97.1 % had SX in LD qn, p< 0.001. Similarly, 49.7% underwent RN in MD qn vs 56.5% had RN in the LD qn, p< 0.001. Greater percentage of pts received CT in MD qn compared to LD qn (44.6% vs 42.1%, p< 0.001). There was a higher percentage of more aggressive cancers such as triple-negative breast cancer (TNBC) and HER2 positive (HER2+) in MD qn compared to LD qn (14.5%, 17.7% vs 11.7%, 16.5% respectively, p< 0.001). In multivariate analysis, in the overall cohort, those who live in AA qn and MD qn have inferior OS and DSS when compared to those who live in LD qn (OS in AA: Hazard Ratio (HR) 1.3, 95% CI: 1.2-1.4; OS in MD: HR 1.2, 95% CI: 1.1-1.3; DSS in AA: HR 1.3, 95% CI: 1.2-1.5; DSS in MD: HR 1.2, 95% CI: 1.1-1.4, all p< 0.001). Similar results in OS and DSS were observed in hormone receptor-positive HER2 negative (HR+) and HER2+ subtypes, but not in TNBC (Table 1). The 5-year OS rates and DSS rates were also comparatively low in AA qn and MD qn compared to LD qn (OS: AA- 84%, MD- 85%, LD- 98%; DSS: AA- 91%, MD- 92%, LD- 95%, all p< 0.001). Conclusion: Early-stage BC pts from areas with worse NDI have poor OS and DSS, after accounting for the demographic, clinicopathological, treatment-related factors. Investments in poor-resource neighborhoods and policies focusing on improving the SES of areas with high deprivation need to be implemented to reduce health care disparities and improve breast cancer outcomes. Table: Overall Survival and Disease Specific Survival Citation Format: Arya Mariam Roy, Anthony George, Kristopher Attwood, Shipra Gandhi. Neighborhood Deprivation Index and Survival in Breast Cancer in the United States [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD1-04.

Abstract GS3-01: GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: Updated results by duration of prior CDK4/6i in metastatic setting

Abstract Background: In patients (pts) with ER+/HER2− metastatic breast cancer (MBC) following progression on prior endocrine and CDK4/6i therapy, the EMERALD trial demonstrated significantly prolonged progression-free survival (PFS) and a manageable safety profile for elacestrant versus standard of care endocrine therapy (SoC). Benefit was observed in all pts and in pts with ESR1 mutant MBC (ESR1-mut). EMERALD is the only oral SERD monotherapy pivotal trial where all pts were pretreated with CDK4/6 inhibitor (CDK 4/6i). Here, we examine the impact of duration of prior CDK4/6i on PFS. Methods: EMERALD (NCT03778931) is a randomized, open-label, phase 3 trial that enrolled pts with ER+/HER2- MBC who previously had 1-2 lines of endocrine therapy, mandatory CDK4/6i, and ≤1 chemotherapy; prior treatment with fulvestrant was allowed. Patients were randomized 1:1 to elacestrant (400 mg orally daily) or SoC (investigator’s choice of aromatase inhibitor or fulvestrant). If randomized to the control arm, patients who received prior fulvestrant were to receive an aromatase inhibitor, and vice versa. If two CDK4/6i were used in the metastatic setting (n=40), the cumulative duration was calculated. Results: A total of 478 pts were randomized (228 with ESR1-mut) between Feb 2019 – Oct 2020 (n=239, elacestrant; n=239, SoC). Overall survival was not yet mature, as of September 2nd 2022. Updated PFS results show statistically significant results in favor of elacestrant, both in all pts and in pts with ESR1-mut. The duration of prior CDK4/6i in the metastatic setting was positively associated with PFS, the longer the duration of prior CDK4/6i in the metastatic setting (n=465), the longer the PFS on elacestrant versus SoC (Table 1). Updated safety data were consistent with previously reported results. Most of the adverse events (AEs), including nausea, were grade 1 and 2, and only 3.4% and 0.9% of the pts discontinued trial therapy because of an AE on elacestrant and SoC, respectively. A low percentage of pts received an antiemetic; 8.0%, 3.7%, and 10.3%, on elacestrant, fulvestrant, and AI, respectively. No hematological safety signal was observed and none of the patients in either of the two treatment arms had sinus bradycardia. Conclusions: EMERALD is the first phase 3 trial to demonstrate a significant PFS improvement versus SoC in all pts and in the subgroup with ESR1 mutations in pts with ER-positive/HER2-negative MBC with 1-2 prior lines of endocrine treatment ± one line of chemotherapy. Elacestrant demonstrated longer PFS versus SOC that was positively associated with the duration of prior treatment with CDK4/6i, which was more pronounced in pts with ESR1-mut MBC. In this 2nd and 3rd line setting, elacestrant was well tolerated with significantly longer PFS versus SoC, highlighting its potential role as a therapeutic option for pts with ER+/HER2- MBC. Table 1: PFS estimates in the elacestrant and SoC arms based on different cut-off points for the duration of prior CDK4/6i. Citation Format: Aditya Bardia, Francois-Clement Bidard, Patrick Neven, Guillermo Streich, Alberto J. Montero, Frederic Forget, Marie-Ange Mouret-Reynier, Joo Hyuk Sohn, Donatienne Taylor, Kathleen K. Harnden, Hung Khong, Judit Kocsis, Florence Dalenc, Patrick Dillon, Sunil Babu, Simon Waters, Ines Deleu, Jose Angel García-Sáenz, Emilio Bria, Marina Elena Cazzaniga, Philippe Aftimos, Javier Cortés, Giulia Tonini, Tarek Sahmoud, Nassir Habboubi, Krzysztof Grzegorzewski, Virginia Kaklamani. GS3-01 EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: Updated results by duration of prior CDK4/6i in metastatic setting [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS3-01.

Abstract P6-01-09: Efficacy of platinum-based chemotherapy and germline mutational status in early-stage triple-negative breast cancer: a unicenter retrospective analysis with long-term follow-up

Abstract BACKGROUND: In early-stage triple negative breast cancer (TNBC), the addition of carboplatin (CBDCA) to neoadjuvant chemotherapy (CT) increases pathologic complete response (pCR) and relapsed-free survival. However, it is unclear whether CBDCA improves overall survival (OS). In addition, the prognostic and/or predictive role of pathogenic germline variants (PGV) in BRCA1/2 genes and other cancer risk in this setting is not fully understood. Here, we assessed the efficacy of (neo)adjuvant CBDCA and the prognostic and predictive role of a panel of 14 genes in patients (pts) with eTNBC. METHODS: This is a retrospective study on 117 pts diagnosed with early-stage TNBC between 2000-2021 at Hospital Clinic of Barcelona. Eighty-one pts (69%) were candidates for PGV testing. Overall, 14 genes (PGV) (BRCA1, BRCA2, PALB2, BRIP1, CHEK2, TP53, ATM, RAD51C, RAD51D, BARD1, MLH1, MSH2, MSH6 and PMS2) were assessed using the TruSight hereditary cancer panel (Illumina MySeq platform) according to local guidelines. Univariable and multivariable logistic regression and Cox regression analyses were performed to identify clinical and molecular predictors of pCR and relapse-free survival (RFS), respectively. Chi-squared or Fisher’s exact tests were used to assess characteristics’ distribution as appropriate. RESULTS: Of 117 pts, 83 (71%) received CT in the neoadjuvant setting and 28 (24%) in the adjuvant setting. CBDCA was added to standard CT in 68 pts (82%) in the neoadjuvant cohort and 7 pts (6%) in the adjuvant cohort. Among pts with germline testing, 32/81 (39%) harbored PGV. BRCA1 was the most frequently mutated gene (18/32, 56%), followed by BRCA2 (5/32, 16%), PALB2 (4/32, 13%), BRIP1 (2/32, 6%), CHEK2, TP53 and PMS2 (3/32, 6%). Percentages of pts receiving CBDCA were similar between patients with and without PGV (14/16,87% and wild type (53/67,79%)(p=0.120). In the neoadjuvant cohort (n=83), CBDCA was the only variable significantly associated with pCR at both univariate (pCR rates of 58.5% with CBCDA and 14.3% without CBCDA; odds ratio [OR]=8.2 [95% CIs 2.0-55.7], p=0.008) and remained statistically significant after adjusting for PGV, tumor size and nodal status (OR=6.9 [95% CIs 1.4-53.0], p=0.028). pCR rates according to PGV are reported in Table 1. In terms of RFS, addition of CBDCA to neoadjuvant therapy (hazard ratio [HR]=0.2 [0.1-0.45], p< 0.001), PGV (HR=0.2 [0.05-0.9], p=0.048), pCR (HR=0.2 [0.1-0.6], p=0.004) and nodal status (HR=5.1 [1.7-15.2], p< 0.003) were significantly associated with RFS in univariate analyses. In a multivariable model, CBDCA remained an independent predictor of improved RFS along with pCR. When the neoadjuvant and adjuvant cohort were pooled together (n=117), platinum-based CT remained significantly associated with better RFS (HR=0.2 [0.14-0.86], p=0.021) regardless of time of administration (i.e., neoadjuvant or adjuvant). With a median follow-up of 5 years, CBCDA use was not found associated with OS (HR=0.7 [0.3-1.8], p= 0.560). CONCLUSIONS: The addition of CBDCA to standard CT was significantly associated with pCR and RFS but not OS, consistent with the phase III data. The benefit in terms of RFS was independent of the presence and the type of pathogenic germline alterations. Table 1. pCR rates according to PGV Citation Format: Adela Rodríguez Hernández, Benedetta Conte, Laia Fernández, Fara Brasó-Maristany, Belén Pastor, Miriam Potrony, Lorena Moreno, Elia Grau, Joan Antón Puig-Butillé, Aurora Sánchez, Blanca González-Farré, Esther Sanfeliu, Olga Martínez-Sáez, Claudette Falato, Maria Vidal, Nuria Chic, Tomás Pascual, Francesco Schettini, Montserrat Muñoz, Francesc Balaguer, Aleix Prat, Barbara Adamo. Efficacy of platinum-based chemotherapy and germline mutational status in early-stage triple-negative breast cancer: a unicenter retrospective analysis with long-term follow-up [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-09.

Abstract P6-01-23: Role of tumor infiltrating lymphocytes and PD-L1 expression in the response to eribulin and pembrolizumab in metastatic triple negative breast cancer (mTNBC) on the ENHANCE1 trial

Abstract Background Treatment with combination chemo-immunotherapy has become the front-line standard for eligible patients with PD-L1 positive mTNBC. PD-L1 is the only approved biomarker for pembrolizumab in metastatic breast cancer for response to combination chemo-immunotherapy, however given that it is not predictive of response in all cases additional biomarkers are needed. Tumor infiltrating lymphocytes (TILs) have been shown to be both predictive and prognostic in operable TNBC, but there are fewer data regarding the role of TILs in mTNBC. In this study we report the associations between TILs and outcomes in patients treated prospectively on the ENHANCE-1 study with eribulin and pembrolizumab. Methods ENHANCE-1 was a single arm phase Ib/II trial which evaluated the efficacy and safety of eribulin and pembrolizumab in 167 patients (pts) with mTNBC who had received 0-2 prior lines of therapy (66 pts in the first line setting [stratum 1] and 101 pts with 1-2 prior lines of therapy [stratum 2]). Objective response rate (ORR) was defined as percentage of pts with either complete response (CR) or partial response (PR) by RECIST 1.1. The ORR was 25.8% in stratum 1 and 21.8% in stratum 2. Stromal TILs (sTIL) and intratumoral TILs were evaluated on whole slide H&E sections from biopsy specimens used for enrollment on ENHANCE-1 by breast pathology according to the International TILs Working Group guidelines. PD-L1 positivity was determined via immunohistochemistry using the Agilent 22C3 antibody. We also assessed TIL density digitally using machine learning classifiers to identify tumor/stromal tissue areas and individual lymphocytes. Results We found that there was statistically significant increase in sTIL counts in responders compared to non-responders in stratum 1 (p=0.002) but not in stratum 2 (p=0.99). We did not find any associations between intratumoral TILs and response. Quantitative PD-L1 scoring via combined proportion score (CPS) was also positively associated with response in stratum 1 (p=0.01) but not in stratum 2 (p=0.34). We also find that sTIL counts are most correlated to CPS scores (continuous) for non-responders within stratum 1 (R2=+0.55, p< 0.01). Conclusion In this population of patients with mTNBC treated prospectively with eribulin and pembrolizumab, sTILs and PDL1 CPS were each individually associated with a positive response in patients treated with front-line combination chemo-immunotherapy. Neither was predictive for patient response in stratum 2. One important caveat is the biopsies were not required immediately prior to enrollment, possibly confounding the tumor microenvironment (TME) at the time of analysis. Our data contribute to emerging data that sTILs can act as a biomarker for response to immune checkpoint inhibition when utilized in the front-line setting for mTNBC. Further characterization of the TME via quantitative immunofluorescence is ongoing. This study was funded by Eisai IIS-E7389 Citation Format: Mathew Kearney, Hua Guo, Rami Vanguri, Qi Wang, Michelle Garlin, Courtney Connelly, Kevin Kalinsky, Eileen P. Connolly. Role of tumor infiltrating lymphocytes and PD-L1 expression in the response to eribulin and pembrolizumab in metastatic triple negative breast cancer (mTNBC) on the ENHANCE1 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-01-23.

Abstract P2-13-05: Triple Negative Breast Cancer (TNBC) patients are more likely to digitally explore clinical trial options and prior to receiving treatment for advanced disease compared to non-TNBC patients

Abstract Introduction: Triple-negative breast cancer (TNBC), an aggressive form of breast cancer (BC) that is associated with poor prognosis, accounts for 10-15% of all BCs. Chemotherapy remains the standard of care (SOC) for advanced disease, with limited clinical benefit. Oncology clinical trials (CTs) are globally recommended and encouraged as the preferred treatment (tx) option for any cancer patient (pt). ‘TrialJectory’ (TJ) is an artificial intelligence (AI)-based technology that matches pts to oncology CTs. Here, we identified distinct characteristics of TNBC pts who signed up to the TJ platform compared to non-TNBC pts. Methods: Using AI and an unsupervised natural language processing approach, the TJ platform clinically matches pts to CTs. Matching is achieved by pt response to an online dynamic questionnaire (www.trialjectory.com) that collects detailed clinical data including clinico-pathologic characteristics, tx history, general health, and comorbidities. Those are compared to the eligibility criteria of available CTs to yield a high-quality actionable matched-trial list. Results: Between 1/2020 and 12/2021, out of 9796 BC pts that signed up, 2688 were TNBC pts (27%). There was no significant difference in age at sign-up between TNBC and non-TNBC patients (median age of 57 years vs 58 years, respectively). Consistently with Non-hispanic black (NHB) race prevalence in the different molecular subtypes in the general US population, NHB race had higher signup rate in TNBC compared to non-TNBC (9.95% vs 5.76%, respectively). TNBC pts signed up at a later disease stage compared to non-TNBC pts (19% of TNBC reported having a stage 1 disease compared to 27% of non-TNBC pts, p< 0.001).A significantly higher percentage of pts with advanced/metastatic TNBC signed up to the TJ platform before starting tx compared to non-TNBC patients (34% vs 22%, respectively, p< 0.001). Furthermore, there was a significant difference in the willingness to travel any distance within the US for a matched clinical trial between TNBC and non-TNBC pts (39% vs 34%, respectively, p< 0.001). Conclusions: In this study, we found significant differences in the characteristics of TNBC vs non-TNBC pts that have signed up to the TJ platform. There was an up to 2-fold enrichment of TNBC on the TJ platform pts compared to their frequency in the general population. While previous studies do not show a difference in stage distribution between different subtypes, TNBC patients initiated their search for CTs at a higher stage. In addition, advanced TNBC patients started their search earlier in their journey, before starting chemotherapy. This may reflect the lack of effective SOC and possibly, the motivation to avoid the use of chemotherapy. This is also supported by the willingness of TNBC patients to travel farther in order to identify and enroll in a CT compared to non-TNBC pts. Importantly, the motivation of TNBC pts to travel any distance has not been reduced despite the COVID-19 pandemic, reflecting a strong drive of this pt population to enroll in CTs. It also demonstrates that with the right access, diverse patient populations are willing to participate in clinical trials. In sum, TNBC pts are more likely to explore CT options, in the advanced stage setting, earlier in their journey. This study demonstrates the power of TJ platform for clinico-pathologic characterization and diverse pt groups, including their drivers and behavioral choices during their battle with cancer. Citation Format: Michal Safran, Yelena Lapidot, Tzvia Bader, Avital Gaziel. Triple Negative Breast Cancer (TNBC) patients are more likely to digitally explore clinical trial options and prior to receiving treatment for advanced disease compared to non-TNBC patients [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-13-05.

Abstract P5-02-14: Identification of mechanisms of acquired resistance to ribociclib plus endocrine therapy using baseline and end-of-treatment circulating tumor DNA samples in the MONALEESA-2, -3, and -7 trials

Abstract Background: Genetic alterations that contribute to resistance to therapy may be acquired during treatment (tx) for hormone receptor−positive/human epidermal growth factor receptor−negative (HR+/HER2−) advanced breast cancer (ABC). A previous pooled analysis of circulating tumor DNA (ctDNA) in MONALEESA (ML)-2, -3, and -7 identified potential predictive biomarkers for response and resistance to ribociclib (RIB) at baseline (BL). Here, we describe an analysis of paired BL and end of treatment (EOT) samples from ML-2, -3, and -7 to identify acquired mechanisms that may impact resistance to RIB + endocrine therapy (ET) vs placebo (PBO) + ET. Methods: ML-2 (NCT01958021), ML-3 (NCT02422615), and ML-7 (NCT02278120) evaluated efficacy and safety of RIB + ET vs PBO + ET in pre- and postmenopausal patients (pts) with HR+/HER2− ABC treated in first-line (1L) and second-line (2L) settings. Plasma samples were collected at cycle 1 day 1 (C1D1; prior to first therapy exposure) and at EOT (± 28 days of recorded progression). ctDNA was sequenced using a targeted next-generation sequencing panel of ≈550 genes. Genes with an alteration frequency of >5% at EOT, regardless of their frequency at BL, were included. Tumor mutational burden (TMB) was assessed by tx arm; a TMB cutoff of 10 mutations/MB was used to categorize pts as TMB high vs low. To assess differences in the presence of alterations, a McNemar test was performed on paired samples and adjusted (adj) for multiple testing using the false discovery rate (FDR). A Bayesian mixed effects model was used to account for ctDNA fraction and trial and to test for tx-specific resistance by including a tx × visit interaction term. Results: A total of 905 paired samples from ML-2, -3, and -7 were included in this analysis, 441 and 464 samples from pts treated with RIB + ET and PBO + ET, respectively. Overall, 17 genes had an alteration frequency of >5% at EOT. The ctDNA fraction was higher at EOT vs C1D1 in both the RIB (P=.037) and PBO (P=.033) arms. The frequency of alterations in RB1 (10.4% vs 2.0%), ATM (11.3% vs 8.4%), FAT1 (4.8% vs 3.0%), and FAT3 (5.0% vs 2.5%) was higher at EOT vs C1D1 in the RIB arm (FDR-adj P<.10). Alterations in ESR1 were also higher at EOT vs C1D1 in both the RIB (26.3% vs 9.1%) and PBO arms (28.9% vs 5.4%) (FDR-adj P<.0001). Conversely, alterations in GATA3 were higher at EOT in the PBO arm (FDR-adj P=.11). These results were consistent after adjusting for ctDNA fraction. The most common ESR1 mutations were D538G, Y537S/N/C/D, E380Q, and L536H/P/R. Tx × visit interaction effects were observed for RB1 in the RIB arm and GATA3 in the PBO arm, suggesting tx-specific resistance. A tx × visit interaction for ESR1 was also observed, suggesting a larger relative increase in ESR1 mutations with PBO vs RIB. The percentage of pts with high TMB (>10) at EOT increased from 1.1% to 5.7% in the RIB arm and from 1.7% to 3% in the PBO arm. After accounting for ctDNA fraction and trial, a larger numerical increase in TMB was observed for RIB (odds ratio [OR], 9.0; 95% CI, 2.9-32.7) vs PBO (OR, 2.1; 95% CI, 0.7-6.5); however, the model did not support a differential tx effect. Conclusions: This comprehensive analysis of pooled samples from ML-2, -3, and -7 identified acquired gene alterations in pts with HR+/HER2− ABC treated with 1L or 2L RIB + ET or PBO + ET. The frequency of several genes known to contribute to resistance (ESR1, RB1, ATM, FAT1, and FAT3) was higher at EOT vs C1D1 in pts treated with RIB + ET, while ESR1 and GATA3 alterations were higher at EOT vs C1D1 in pts treated with PBO + ET. This paired dataset of BL and EOT samples from pts with HR+/HER2− ABC treated with a CDK4/6 inhibitor and ET is the largest to date and could be used to validate and confirm acquired resistance mechanisms with low alteration frequency. Citation Format: Fabrice Andre, Nadia Solovieff, Faye Su, Aditya Bardia, Patrick Neven, Yoon-Sim Yap, Debu Tripathy, Yen-Shen Lu, Dennis Slamon, Stephen K. Chia, Mukta Joshi, Arunava Chakravartty, Agnes Lteif, Tetiana Taran, Carlos Arteaga. Identification of mechanisms of acquired resistance to ribociclib plus endocrine therapy using baseline and end-of-treatment circulating tumor DNA samples in the MONALEESA-2, -3, and -7 trials [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-02-14.

Abstract PD13-07: PD13-07 Combination therapy with the AKT inhibitor, ipatasertib, endocrine therapy, and a CDK4/6 inhibitor for hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC): results from the phase I TAKTIC trial

Abstract Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) provide significant clinical benefit in patients with HR+/HER2- metastatic breast cancer (MBC) and have become a standard of care treatment. Prior insights from tumor profiling and preclinical analyses suggest that AKT1 activation can induce CDK4/6i resistance. We hypothesized that targeting AKT1 following CDK4/6i progression may be an effective therapeutic strategy and conducted a clinical trial to evaluate both doublet (ET+AKTi) and triplet (ET+AKTIi+CDK 4/6i) therapy in the ≥ 2nd line MBC setting. Methods: TAKTIC is an open-label phase Ib clinical trial (clinicaltrials.gov NCT03959891) evaluating the combination of the AKT inhibitor ipatasertib (ipat) with fulvestrant (Arm A), an aromatase inhibitor (Arm B), or the triplet combination (Arm C) with fulvestrant + palbociclib (palbo). The primary objective is to evaluate the safety (NCI CTCAE 5.0) and tolerability of ipat in combination with endocrine therapy +/- CDK4/6i. Secondary objectives include clinical efficacy, as determined by objective response rate (RECIST v1.1), clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). Key inclusion criteria include unresectable HR+/HER2- MBC; at least 1 prior therapy for MBC including any CDK4/6i; up to 2 prior lines of chemotherapy for MBC (no limit on prior endocrine therapy). Here, we present an updated interim analysis from all study arms. Results: The trial completed accrual with 77 pts enrolled from June 2019 – February 2022, including 19 on Arm A, 16 on Arm B, and 42 on Arm C. Median age was 62 (range 32-88) and 65/77 pts (84%) received prior CDK4/6i (median no. of prior lines = 3, range 1-13). 56/77 pts (73%) had measurable disease at baseline and 50/77 pts (65%) had visceral metastases in the liver/lung (68% Arm A, 44% Arm B, 71% Arm C). Pts enrolled on Arms A and B received ipat at 400mg in combination with fulvestrant or an aromatase inhibitor, respectively. In Arm C, 27/42 pts enrolled into the dose escalation phase and received ipat + palbo at varying doses in combination with fulvestrant. Two DLTs were observed in the 300mg ipat + 125mg palbo cohort (grade 4 neutropenia ≥ 7 days). ET+400mg ipat + 100mg palbo was determined to be the recommended phase 2 dose (R2PD), and the remaining 15/42 pts on Arm C were treated at this dose level in the expansion phase. Treatment was well tolerated in all arms. Grade 3 and 4 toxicities included neutropenia (39/77, 50.6%), leukopenia (15/77, 19.5%), diarrhea (11/77, 14/3%), transaminitis (7/77, 9.1%), lymphopenia (6/77, 7.8%), rash (6/77, 7.8%), and thrombocytopenia (3/77, 3.9%). As of 6/28/2022, 16/77 pts remain on treatment. The median treatment duration for all pts is estimated at 6 months (range 0.5-39). Among the 56 pts with measurable disease, 11 had partial response (PR) and 32 had stable disease (SD) as the best response. CBR, defined as percentage of pts who achieved PR or SD > 6 months, was 48% across the study (53% Arm A, 31% Arm B, 57% Arm C). The median PFS was 5.5 months (95% confidence interval [CI]: 3.8 – 7.4) and the median OS was 24.5 months (95% CI: 17.1 – 33.9). Conclusions: The combination of ipat with endocrine therapy +/- palbo is well tolerated in heavily pre-treated pts, with preliminary evidence of clinical activity. This trial demonstrates how molecular insights related to CDK4/6i resistance inform potential therapy combinations. Further studies are needed to evaluate AKTi-based combinations in pts with HR+ MBC. Citation Format: Seth A. Wander, Jennifer C. Keenan, Andrzej Niemierko, Dejan Juric, Laura M. Spring, Jeffrey Supko, Neelima Vidula, Steven J. Isakoff, Lianne Ryan, Sarah Padden, Elizabeth Fisher, Amber Newton, Beverly Moy, Leif Ellisen, Douglas S. Micalizzi, Aditya Bardia. PD13-07 Combination therapy with the AKT inhibitor, ipatasertib, endocrine therapy, and a CDK4/6 inhibitor for hormone receptor positive (HR+)/HER2 negative metastatic breast cancer (MBC): results from the phase I TAKTIC trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD13-07.