Inhibitor Therapy Research Articles

Improvement in clinical features of hypercortisolism during osilodrostat treatment: findings from the Phase III LINC 3 trial inCushing's disease.

Cushing's disease is associated with substantial morbidity and impaired quality of life (QoL) resulting from excess cortisol exposure. The current study explored improvements in clinical signs and additional specificmanifestations of hypercortisolism during osilodrostat (potent oral 11β-hydroxylase inhibitor) therapy by degree of control of mean urinary free cortisol (mUFC). LINC 3 (NCT02180217) was a prospective, open-label, 48-week study of osilodrostat (starting dose: 2mg bid; maximum: 30mg bid) that enrolled 137 adults with Cushing's disease and mUFC > 1.5 times the upper limit of normal (ULN). mUFC (normal range 11‒138nmol/24h), cardiometabolic parameters (blood pressure, weight, waist circumference, body mass index, total cholesterol, fasting plasma glucose, glycated haemoglobin), physical manifestations of hypercortisolism (facial rubor, striae, fat distribution, bruising, hirsutism [females], muscle atrophy) and QoL were evaluated. mUFC was defined as controlled if ≤ ULN, partially controlled if > ULN but ≥ 50% reduction from baseline, and uncontrolled if > ULN and < 50% reduction from baseline. Concomitant medications were permitted throughoutthe study. At weeks 24 and 48, respectively, mUFC was controlled in 93 (67.9%) and 91 (66.4%) patients, partially controlled in 20 (14.6%) and 13 (9.5%), and uncontrolled in 24 (17.5%) and 33 (24.1%). Overall, mean improvements from baseline in cardiometabolic at week 24 were greater in patients with controlled or partially controlled versus uncontrolled mUFC; at week 48, improvements occurred irrespective of mUFC control. Generally, physical manifestations and QoL progressively improved from baseline irrespective of mUFC control. Improvements in clinical signs and additional specificmanifestations of hypercortisolism associated with Cushing's disease occurred alongside decreases in mUFC. Trial registration NCT02180217 (first posted July 2014).

Abstract PO2-19-12: Enhancing skin appearance and quality of life in breast cancer survivors on aromatase inhibitor therapy

Abstract Background: Post-menopausal women with estrogen receptor positive breast cancer (BC) are typically prescribed endocrine therapy with an aromatase inhibitor (AI) for 5-10 years following BC diagnosis. AIs have multiple established side effects related to estrogen deprivation including vasomotor symptoms, vaginal dryness, and accelerated bone thinning. Many patients also complain about the impact of AIs on skin quality; however, limited data currently exists, particularly with objective measurements of skin quality. Canfield Sciences VISIA-CA is a device that can be used to objectively measure skin changes using patented comparison to norms analysis with a skin feature database to grade the skin relative to others in the same age and skin type. Herein, we aim to evaluate changes in skin quality with the Canfield Sciences VISIA-CA Device after initiation of AI therapy and investigate potential benefits of skincare intervention. Trial Design: This is a pilot study aiming to describe changes in skin quality after initiation of AI therapy in BC survivors through use of VISIA-CA technology and patient reported outcome measures. This study will allow us to collect data and identify the trend (if any) for a future larger study. Patients who consent for participation are given a baseline survey to assess self-reported quality of life, perception of skin quality, and self-image prior to initiation of AI. Patients also receive baseline skin measurement with the VISIA-CA device and facial skin photography. Baseline skincare regimen is documented. Any patients on prescription tretinoin products at time of baseline assessment are excluded from the study. Patients return 6 months after initiation of AI for follow-up surveys, updated VISIA-CA measurement, and facial skin photography. Patients then meet with a Mayo Clinic Cosmetic Center aesthetician for skincare intervention with recommended topical treatments including daily facial cleanser, exfoliator, toner, hydrating crème, and retinol-based product. Patients return for additional visits with updated survey, VISIA-CA measurement, and facial skin photography at 1 month, 3 months, and 6 months after skincare intervention. Patients are asked to complete skincare compliance diary to document adherence on a weekly basis. Eligibility Criteria: Post-menopausal patients with newly diagnosed ER-positive BC at Mayo Clinic Florida are identified for participation in the study prior to beginning AI therapy. Specific Aims: 1.) Evaluate the incidence and severity of skin changes after initiation of AI therapy in BC survivors through use of Canfield Sciences VISIA-CA technology, facial skin photography, and validated patient reported outcome measures. 2.) Assess for objective improvements in skin quality measurements after skincare intervention including a retinol-based product Statistical Methods: Continuous variables will be summarized as mean (standard deviation) or median (range) and categorical variables will be reported as frequency (percentage). The changes of skin measurement and patient reported outcome measurements will be calculated and summarized for the following time frames: 1) from initiation of AI therapy to 26 weeks after 2) from the initiation of skincare intervention and 4 weeks, 12 weeks, and 26 weeks after. Appropriate statistical plots will be used to illustrate the change. Target Accrual: 50 patients. Schedule of Events Citation Format: Lauren Cornell, Leila Tolaymat, Pooja Advani, Saranya Chumsri, Pincelli Thais. Enhancing skin appearance and quality of life in breast cancer survivors on aromatase inhibitor therapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-19-12.

Abstract PO2-12-10: Age-specific outcomes in breast cancer patients treated with aromatase inhibitors - A national inpatient sample database analysis

Abstract Background: This study aims to investigate the age-specific outcomes of breast cancer patients undergoing aromatase inhibitors therapy. Currently, no research exists on the age-specific differences in outcomes for this patient population. This study seeks to fill this knowledge gap and provide valuable insights into the various outcomes of these patients. Methods: This retrospective study analyzed hospitalization data from the National Inpatient Sample (NIS) between January 2016 and December 2019 using STATA/BE 17.0 for statistical analysis. It focused on breast cancer patients treated with aromatase inhibitors, evaluating outcomes like mortality, length of stay, charges, and clinical outcomes. We used univariate regression and logistic analysis, with ICD-10 codes utilized for data classification. Results: A total of 5,994 weighted hospitalizations were identified, consisting of breast cancer patients being treated with aromatase inhibitors. For patients aged below 65 (n=1,919), the inpatient mortality rate was 1.8% (n=35), while for patients aged 65 and above (n=4,075), it was slightly higher at 2.3% (n=94). However, there was no statistically significant difference in inpatient mortality between the two age groups (adjusted odds ratio [aOR] = 1.21 [0.82-1.78], p=0.339). The average length of stay (LOS) was similar for both age groups, with patients below 65 having a mean LOS of 4.75 days and those aged 65 and above having a mean LOS of 4.71 days. Total charges ($) in the younger population ( &amp;lt; 65) were incurred at a mean of $60,782.73 (56,764.18-64,801.27), compared to lesser charges in the elderly at a mean of $54,734.38 (52,339.83-57,128.94). The occurrence of pathological fractures was higher in patients below 65, with a rate of 1.6% (n=31), compared to 0.8% (n=33) in patients aged 65 and above (aOR = 0.47 [0.28-0.78], p=0.004). Regarding venous thromboembolism (VTE), the occurrence was 5.5% (n=105) in patients below 65 and 4.8% (n=195) in patients aged 65 and above. There was no significant difference between the two age groups (aOR = 0.86 [0.68-1.10], p=0.237). The occurrence of acute cerebrovascular accidents (CVA) was 0.6% (n=11) in patients below 65 and 1.6% (n=65) in patients aged 65 and above, with an aOR of 2.58 (1.38-4.80), indicating a significantly higher likelihood of CVA in the older age group (p=0.003). Patients aged 65 and above had a higher occurrence of myocardial infarction (MI) compared to patients below 65, with rates of 2.1% (n=85) and 0.1% (n=2), respectively. The aOR for MI was 2.35 (1.39-3.98), indicating a significantly higher likelihood of MI in the older age group (p=0.001). There was no statistically significant difference in the occurrence of hypertensive crisis (HTN crisis) between the two age groups (aOR=1.47 [0.93-2.34], p=0.09). Conclusion: Among breast cancer patients receiving aromatase inhibitors, there was no significant difference in in-patient mortality between those aged below 65 and those aged 65 and above. Both age groups had similar lengths of stay and charges incurred. There was no statistically significant difference in VTE and HTN crisis odds. However, patients below 65 had a higher occurrence of pathological fractures, while patients aged 65 and above had a higher likelihood of acute cerebrovascular accidents and myocardial infarction. Further guidelines must be established to improve inpatient morbidity and mortality in this patient population. Breast cancer patients on aromatase inhibitors therapy Citation Format: Rushin Patel, Akshit Chitkara, Zalak Patel, Mrunal Patel, Darshil Patel, Himanshu Kavani, FNU Anamika, Femina Patel. Age-specific outcomes in breast cancer patients treated with aromatase inhibitors - A national inpatient sample database analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-12-10.

Abstract PO5-03-03: Nomogram for predicting brain metastasis in early-stage breast cancer patients

Abstract Nomogram for predicting brain metastasis in early-stage breast cancer patients Background: Brain metastasis is a significant concern for patients with early-stage breast cancer, as it can have a detrimental impact on survival and quality of life. Clinical and pathological characteristics of the primary tumor may be modeled into a nomogram that can predict the risk of brain metastasis. The goal is to create a nomogram and clinical calculator to assist in selection of patients with high risk of brain metastasis to enrich patient population for accrual on clinical trials for the purpose of preventing or delaying emergence of brain metastasis, at an early stage of their disease. Methods: We reviewed all early-stage breast cancer patients (stages I to III) N=40290 from the University of Texas MD Anderson Cancer Center, Houston, TX, from 1/1/1997 to 5/8/2020. We utilized multiple predictive statistical models to identify the most relevant variables and optimal predictive criteria. Variables for the model included patient age, tumor characteristics (such as grade,hormone receptor and HER2 status) and medical treatment (such as chemotherapy and endocrine therapy). The Receiver Operating Characteristic (ROC), and its AUC (area under the curve) was used to demonstrate the performance of the multivariate model to predict the occurrence of brain metastasis at different time points (1 year, 2 years, and 5 years), distinguishing between patients who develop brain metastasis in a time-dependent manner and those who do not. Results: The results showed the following clinical variables to be statistically significant in predicting brain metastasis: younger age, high estrogen and progesterone receptor percentage, higher tumor size; use of aromatase inhibitor therapy, and use of selective estrogen receptor modulator therapy were associated with a decreased risk of brain metastasis. Higher grade, Ki-67 levels, HER2-positive status, lymphovascular invasion and the use of chemotherapy was associated with an increased risk. The AUC values for the prediction of brain metastasis at different time points are as follows: 0.85 at 1 year, 0.83 at 2 years, and 0.82 at 5 years. These values indicate that the multivariate model has good discriminative ability, with higher values indicating a better predictive performance. An AUC of 0.85 suggests that the model has a high probability of correctly distinguishing between patients who will develop brain metastasis and those who will not at 1 year. Conclusions: Our predictive tool holds promise in assisting clinicians when making informed, personalized care decisions for patients at risk of developing brain metastasis. The model will be validated using independent patient cohorts from Institut Jules Bordet, Brussel, Belgium, to assess their accuracy and reproducibility. Continued research and validation will further refine these models, increasing their reliability and their clinical/clinical research applicability. Citation Format: Akshara Singareeka Raghavendra, Nuria Kotecki, Kristofer Jennings, Ottavia Amato, Debu Tripathy, Ahmad Awada, Nuhad Ibrahim. Nomogram for predicting brain metastasis in early-stage breast cancer patients [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-03-03.

Abstract PO4-19-05: OptimICE-pCR: De-escalation of therapy in early-stage TNBC patients who achieve pCR after neoadjuvant chemotherapy with checkpoint inhibitor therapy (Alliance A012103)

Abstract Background: For patients with stage II-III triple-negative breast cancer (TNBC), standard of care systemic therapy consists of neoadjuvant pembrolizumab with chemotherapy, followed by 27 weeks of adjuvant pembrolizumab based on the results of the phase III KEYNOTE-522 trial. This trial demonstrated that pathologic complete response (pCR) rates and event-free survival (EFS) were significantly better among patients who received neoadjuvant followed by adjuvant pembrolizumab in addition to chemotherapy compared to chemotherapy alone. An exploratory analysis from this study demonstrated better EFS among patients who experienced a pathologic complete response (pCR) to neoadjuvant therapy compared to those with residual disease. Additionally, other studies, including GeparNuevo, which did not include adjuvant checkpoint inhibition, demonstrated EFS benefit from the addition of preoperative checkpoint inhibitor therapy to chemotherapy. It is therefore unclear if adjuvant pembrolizumab improves outcomes for patients with early-stage TNBC who achieve a pCR after neoadjuvant pembrolizumab plus chemotherapy. OptimICE-pCR trial utilizes response to preoperative therapy to tailor adjuvant therapy, and the goal is to determine whether patients who achieve pCR to pembrolizumab plus chemotherapy can achieve a similar recurrence-free survival (RFS) with observation compared to adjuvant pembrolizumab monotherapy Methods: OptimICE-pCR is an open-label, multicenter, randomized phase III trial that is enrolling patients with stage T1cN1-2 or T2-4N0-2 TNBC. To be eligible, patients must have experienced a pCR after the completion of neoadjuvant therapy containing a minimum of six cycles of chemotherapy in combination with pembrolizumab. Participants are randomized 1:1 to receive either 27 weeks of adjuvant pembrolizumab or to observation. Participants on the pembrolizumab arm receive pembrolizumab 200 mg IV on day 1 of each 21-day cycle for 9 cycles, or 400 mg IV on day 1 of each 42-day cycle for 4 cycles, followed by one dose of 200 mg IV every 21 days. The primary objective is to evaluate whether observation results in non-inferior RFS compared to adjuvant pembrolizumab. Non-inferiority is defined as an estimated 3-year RFS of 91% or higher in the observation arm compared to 94% in the pembrolizumab arm. The total sample size will be 1,295 patients, which will provide 80% power at one-sided significance level of 0.05 to detect this difference, which corresponds to a non-inferiority hazard ratio of 1.52. Key secondary endpoints include overall survival, locoregional recurrence, quality of life, financial toxicity, work productivity impairment, cost-effectiveness, and safety and tolerability. Key correlative objectives include detection of ctDNA at baseline and association with RFS and association of key biomarkers (TILs, PDL1, immune gene expression) from the primary tumor with RFS. The trial is currently open and enrolling patients. Support: U10CA180821, U10CA180882; U24 CA196171; U10CA180820 (ECOG-ACRIN); U10CA180863 (CCTG); https://acknowledgments.alliancefound.org. ClinicalTrials.gov Identifier: NCT05812807 Citation Format: Sara Tolaney, Karla Ballman, Charles M Perou, David Cescon, Margaret Gatti-Mays, Victoria Blinder, Shoshana Rosenberg, Elizabeth Mittendorf, Anna Weiss, Hope Rugo, Alice Ho, Dana Casey, Baljit Singh, Fabrice Smieliauskas, Yara Abdou, Vijay Damarla, Jane Meisel, Lisa Carey, Ann Partridge. OptimICE-pCR: De-escalation of therapy in early-stage TNBC patients who achieve pCR after neoadjuvant chemotherapy with checkpoint inhibitor therapy (Alliance A012103) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-05.

Abstract PS14-07: Exploring Circulating Leukocyte RNA Expression: Implications for Treatment Outcomes and Immune-Related Adverse Events in Patients with Triple Negative Breast Cancer Enrolled in the GeparNuevo Trial

Abstract Abstract Exploring Circulating Leukocyte RNA Expression: Implications for Treatment Outcomes and Immune-Related Adverse Events in Patients with Triple Negative Breast Cancer Enrolled in the GeparNuevo Trial Background: Significant research has been conducted on the influence of immune checkpoint inhibitor therapy on tumor microenvironment, particularly with regard to tumor-infiltrating immune cells. Nevertheless, our understanding of the circulating immune repertoire and its association with treatment outcomes remains limited. Consequently, our subproject of the GeparNuevo trial aimed to explore the RNA phenotype of circulating leukocytes and its impact on overall survival (OS), and adverse events of patients enrolled in the GeparNuevo trial (Loibl S et al. Annals Oncol 2022). Methods: The GeparNuevo phase II trial focused on the effects of neoadjuvant nab-paclitaxel followed by epirubicin/cyclophosphamide (nabP-EC) chemotherapy combined with the anti-PD-L1 immune checkpoint inhibitor durvalumab versus placebo in patients with non-metastatic triple-negative breast cancer. RNA-stabilizing PAXgene tubes were used to collect blood samples prior to treatment initiation. RNA was extracted from circulating leukocytes of 117 patients and analyzed using a custom NanoString nCounter CodeSet, including 290 immune-related target genes. The associations between 16 immune cell scores, 26 immune signaling scores, 31 individual gene expression patterns, OS, and immune-related adverse events (irAEs) were analyzed. Results: Univariate Cox regression analysis using continuous scores revealed a significant correlation between PIP3 activates AKT signaling, T cells, CDK2, and TIMP1 expression with OS in the placebo arm. Higher expression of PIP3 activates AKT signaling, T cells, and CDK2, as well as lower expression of TIMP1, were associated with prolonged survival. Notably, T cell scores and CDK2 expression exhibited a significant interaction with the treatment arm (p=0.0489 and 0.0210, respectively). Multivariate Cox regression analysis demonstrated a significant association of DPP4, ICOS and MYC expression with OS. Additionally, CDK2, CDKN2A, F5 and HLA-DRA expression were linked to the presence of irAEs. In the durvalumab arm, TNFR2 non canonical NFkB pathway signaling, CDK2 and CDKN2A expression showed an inverse association with the occurrence of irAEs. Conclusions: Our study provides preliminary evidence that RNA derived from circulating leukocytes may serve as a potential biomarker for predicting treatment outcomes and identifying patients prone to develop side effects during standard-of-care chemotherapy or immune checkpoint therapy. These findings highlight the potential utility of peripheral immune cell RNA profiling in improving treatment strategies and patient management. Further research and validation are necessary to fully comprehend the clinical significance and broader implications of these findings. Citation Format: Hanna Hübner, Matthias Ruebner, Andreas Schneeweiss, Carsten Denkert, Hans-Peter Sinn, Michael Braun, Thomas Karn, Bruno V. Sinn, Dirk-Michael Zahm, Jörg Thomalla, Jens Huober, Claus Hanusch, Michael Untch, Christine Solbach, Theresa Link, Natalie Filmann, Julia Rey, Johannes Holtschmidt, Sibylle Loibl, Peter A. Fasching. Exploring Circulating Leukocyte RNA Expression: Implications for Treatment Outcomes and Immune-Related Adverse Events in Patients with Triple Negative Breast Cancer Enrolled in the GeparNuevo Trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS14-07.

Abstract PS06-04: The prognostic and predictive impact of circulating tumour DNA (ctDNA) dynamics in patients with metastatic Triple Negative Breast Cancer (TNBC) on olaparib based therapy: Results from Cohort E of the PlasmaMATCH trial

Abstract Background: Early changes in ctDNA levels, ctDNA dynamics, may help identify which patients are responding to therapy earlier than imaging. Few studies have assessed ctDNA dynamics during PARP inhibitor therapy. Here we report paired baseline and early on treatment ctDNA analysis from cohort E of plasmaMATCH, that recruited patients with TNBC to treatment with olaparib (PARP inhibitor) plus ceralasertib (ATR inhibitor). Methods: The plasmaMATCH trial assessed the ability of ctDNA testing to allocate patients to mutation matched treatment cohorts (A-D). Patients with TNBC, and without mutations matching cohorts B-D, were enrolled on cohort E. Samples were collected for ctDNA analysis pre-treatment at cycle 1-day1 (C1D1) and cycle 2-day 1 (C2D1). A minimum of 14 days of treatment in the first cycle was required for inclusion in this analysis. Samples were sequenced using error-corrected gene targeted panels (Guardant360, or GuardantOMNI, Guardant Health). Circulating DNA ratio (CDR) was calculated as the ratio of C2D1 ctDNA level to C1D1, pre-specified using the weighted mean of variant allele fractions (AF) of clonal mutations at C1D1, excluding variants with AF &amp;lt; 0.3%, and variants in genes frequently mutated in clonal haematopoesis (GNAS, JAK2, IDH1, IDH2 and ATM). The optimal cut-point for predicting progression free survival (PFS) was assessed as the cut-point with the highest Harrell’s C-index. Results: Of the 75 patients that were enrolled into cohort E, 53 patients had samples sent for paired C1D1-C2D1 ctDNA sequencing, 2 failed sequencing, and all 51 (68%) patients had detectable ctDNA at C1D1. The ctDNA analysis set was representative of the overall enrolled population. The optimal ctDNA dynamics C-index cut-point for predicting PFS was 0 (undetectable ctDNA at C2D1). Median PFS with ctDNA CDR &amp;gt;0 (detectable ctDNA at C2D1) was 4.3 months (95% CI 2.4-5.8), and with undetectable ctDNA was 12 months (95% CI 8-NA) (HR 4.02, 95% CI 1.22-13.23, p=0.01). Splitting patients by median CDR was not predictive (HR=0.98; 95%CI: 0.52-1.82, p=0.94). Confirmed objective response rate was 85.7% (42.1-99.6) in patients with undetectable ctDNA at C2D1, and with detectable ctDNA was 11.4% (3.8-24.6) (OR 4.02, 95% CI 1.22-13.23, p=0.01). Of the 7 patients with undetectable ctDNA at C2D1, one had a BRCA2 germline mutation, and all other patients were wildtype for BRCA1/2 mutations in tumour and germline. All patients with undetectable ctDNA and BRCA1/2 wildtype had a confirmed response.In cohorts A-D (mutation targeted therapies, in predominantly ER positive cancer), the optimal ctDNA dynamics C-index CDR cut-point was 0.165 (HR 3.44, 95%CI: 2.06-5.75, p&amp;lt; 0.001), with median CDR cut-point also highly predictive (HR=2.14, 95%CI:1.36-3.36, p=0.001). Undetectable ctDNA was also strongly predictive (HR=4.41; 95%CI: 1.97-9.87, p&amp;lt; 0.001) in cohort A-D.In cohort E, a significant association was found between baseline ctDNA and PFS, with an optimal C-index cutpoint of 6.81% (HR=3.02, 95% CI: 1.39-6.56, p=0.001). Median PFS for baseline ctDNA ≤ 6.81% was 10.2 months (95% CI 3.7-17.2), and for baseline ctDNA &amp;gt;6.81% was 4.4 months (95% CI 2.2-5.5). Conclusions: ‘Clearance’ of ctDNA to become undetectable at C2D1 identified sporadic TNBC patients who benefited from olaparib and ceralasertib. Although ‘clearance’ of ctDNA was associated with good outcome on olaparib plus ceralasertib, median CDR was not predictive of treatment benefit. This contrasts the results of ctDNA dynamic assessment of cohort A-D, where median CDR was highly predictive of treatment benefit. ctDNA dynamic assessment may differ between mutation targeted therapies (cohorts A-D) that induce cell-cycle arrest, and PARP inhibitors (cohort E) that inhibit DNA repair mechanisms. Implementing ctDNA dynamics into clinical trials and care may require distinct analysis for different therapies. Citation Format: Iseult Browne, Javier Pascual, Rosalind Cutts, Belinda Kingston, Sarah Hrebien, Lucy Kilburn, Alex Pearson, Laura Moretti, Andrew Wardley, Iain Macpherson, Richard Baird, Rebecca Roylance, Iris Faull, Kimberly C Banks, Isaac Garcia-Murillas, Judith Bliss, Alistair Ring, Nicholas Turner. The prognostic and predictive impact of circulating tumour DNA (ctDNA) dynamics in patients with metastatic Triple Negative Breast Cancer (TNBC) on olaparib based therapy: Results from Cohort E of the PlasmaMATCH trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS06-04.

Abstract PO5-21-06: Pathway profiling for prediction of response to neoadjuvant Letrozole therapy in ER positive postmenopausal breast cancer: gaining new insights for targeted treatment

Abstract Introduction: The NEOLBC (NCT03283384) study included postmenopausal patients with hormone receptor positive (ER≥50%, PR any), HER2 negative, stage II/III breast cancer. A baseline biopsy was taken prior to start letrozole treatment and after two weeks of treatment. Based on the two week Ki67-IHC, patients were randomized (Ki67 ≥1%) to receive either Letrozole + Ribociclib or standard chemotherapy until surgery, or continued (Ki67 &amp;lt; 1%) Letrozole mono therapy. Here we describe the signal transduction pathway profiles to better understand the molecular mechanisms of response to neoadjuvant letrozole. Methods: Signal transduction pathway activities for the ER, AR, MAPK, PI3K, HH, TGFβ and Notch pathways were measured on baseline and two weeks samples using the OncoSIGNal qPCR test (InnoSIGN). High pathway activity in a tumor sample was defined as pathway activity value above the 95th percentile of reference normal epithelial breast tissue. The pathway activity patterns of the Ki67 &amp;lt; 1% (n=30) and Ki67 &amp;gt; 1% (n=63) groups were compared between baseline and two weeks of treatment. Results: Although all measured baseline samples (n=93) were ER IHC staining positive (≥50%), there is a large range in baseline ER signal transduction pathway activity (32 to 78 on a scale from 0 – 100) and 20% of the samples show an ER-activity range (32 - 45) that normally falls in the range of ER IHC stained negative breast tissue. The group with Ki67 &amp;gt; 1% after 2 weeks Letrozole treatment showed non elevated ER pathway activity at baseline more often (25%) compared to the Ki67 &amp;lt; 1% group (10%). 92% of the patients showed a decrease in ER pathway (11.6 ± 8.6) activity after 2 week letrozole treatment compared to baseline (p=8.5e-13). Interestingly, baseline AR pathway activity has a good differentiating predictive value for the two week response to letrozole treatment and the overall AR pathway activity score was higher in the low Ki67 group (51.4 ± 7.4) than in the Ki67 ≥ 1% group (46.7 ± 6.4; p=0.0053) and more often classified as high in 30% of the low Ki67 group vs. 13% of the Ki67 ≥ 1% group. The Ki67 &amp;gt; 1% group showed activation of non-hormonal pathways (PI3K, MAPK and/or HH) more frequent (38%) at baseline compared to the &amp;lt; 1% Ki67 group (19%). Conclusion: Positive ER staining does not always relate to a high ER pathway activity, possibly explaining that not all patients respond equally well to ER inhibition therapy. Activation of hormonal pathways (ER, but also AR) appear to be predictive for early (2 weeks) response towards Letrozole as assessed by Ki67 staining. Involvement of non-hormonal pathways is associated with less effective response towards Letrozole alone. Pathway activity patterns could improve insight to underlying hormonal treatment escape mechanisms which could lead to alternative treatment options in patients with ER-positive breast cancer. Citation Format: Nadia de Gruil, Anne Florine de Groot, Yvonne Wesseling-Rozendaal, Diederick Keizer, Sigi Neerken, Judith Kroep. Pathway profiling for prediction of response to neoadjuvant Letrozole therapy in ER positive postmenopausal breast cancer: gaining new insights for targeted treatment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-21-06.

Abstract PO3-29-01: Defining the molecular-genetic mechanism of CDK4/6 inhibition therapy induced senescence to identify biomarkers and determine how senescence contributes to patient outcomes

Abstract In the context of ER+ breast cancers the CDK4/6i have had extraordinary success extending the duration of median PFS, and in some cases, OS, particularly in combination with hormone antagonists.Still there are several individuals who do not have good clinical responses or can only maintain these for a short period of time and then resistance manifests.One challenge to improving patient outcomes by combining CDK4/6i with other modalities is our incomplete understanding of how they induce these beneficial outcomes at the cellular and molecular level.For example, while a few mutations associated with resistance prevent induction of cell cycle exit by the drug, simply inducing cell cycle exit does not explain the positive activity of CDK4/6i. Additional mechanisms such as drug induced enhancement of MHC class I antigen presentation on the surface of treated cancer cells to non-cancer cell autonomous effects on the development of Tregs may also contribute.CDK4/6i can also induce cellular senescence in cancer cell lines in vitro and in mouse models of cancer.Senescence is a cell fate transformation whereby the cell ‘differentiates’ into a stably-arrested, inflammation-provoking cell fate through a largely poorly understood developmental pathway. However, identification of stably arrested and inflammation provoking cells, particularly in human biopsies, has been a pernicious challenge.This might be overcome by identifying the molecular and genetic basis of how senescent cells arise from non-cycling quiescent cells, and two developmental studies, one, carried out in dedifferentiated liposarcoma cell lines treated with CDK4/6i and another during DNA damage induced senescence in primary fibroblasts have begun to do this.These showed that the canonical markers used in the laboratory, such as the accumulation of the CDK inhibitor p16Ink4a or the accumulation of senescence associated beta-galactosidase positive cells, arise well before cells underwent stable arrest.Furthermore, it is now universally acknowledged that the idiotypic heterogeneous nature of the expression of the various cytokines and growth factors that are part of the senescence-associated secretory program, precludes the use of transcripts and proteins culled from lists of gene products associated with senescence in other systems.Thus, the limited analysis of therapy induced senescence in breast cancer cell lines has prevented the evaluation of how this biology, induced by CDK4/6i, might contribute to disease management. We had pioneered the approach to identify late-appearing necessary regulators that control the fate transition from reversible to stable arrest in dedifferentiated liposarcoma. This insight was then used to identify senescent cells in patients and address the contribution that senescence makes over time. In this presentation we will describe similar but as of yet unpublished work describing the detailed temporal molecular genetic analysis of CDK4/6i therapy induced senescence in ER+ breast cancer cell lines, and discuss how we have nominated highly specific late markers of cellular senescence for application in a number of archival and ongoing clinical trials to determine (1) whether therapy induced senescence contributes to disease management and (2) how its contributions change over time.Such insights will further inform patient care and also drive research in model organisms to unravel the complex role that senescence plays in breast cancer development and therapy. Citation Format: Marimar Benitez, Rei Kudo, Caroline Gleason, Sarat Chandarlapaty, Andrew Koff. Defining the molecular-genetic mechanism of CDK4/6 inhibition therapy induced senescence to identify biomarkers and determine how senescence contributes to patient outcomes [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-29-01.

Identification of ATM Mutation as a Potential Prognostic Biomarker for Immune Checkpoint Inhibitors Therapy

Background: Ataxia telangiectasia mutated (ATM), an apical DNA damage response gene, is a commonly mutated gene in tumors, and its mutation could strengthen tumor immunogenicity and alter the expression of PD-L1, which potentially contributes to immune checkpoint inhibitors (ICIs) therapy. Methods: The characteristics of ATM mutation and its relationship with the ICIs-treated clinical prognosis have been analyzed comprehensively in this paper. The overall frequency of ATM mutations has been found to be 4% (554/10953) in the cancer genome atlas (TCGA) cohort. Results: Both the TMB and MSI levels in patients with ATM mutations were significantly higher than those in patients without mutations (P &lt; 0.0001). The median TMB was positively correlated with the frequency of ATM mutations (r = 0.54, P = 0.003). In the TCGA cohort, patients with ATM mutations had better clinical benefits in terms of overall survival (OS, hazard ratio (HR) = 0.736, 95% CI = 0.623 - 0.869), progression-free survival (PFS, HR = 0.761, 95% CI = 0.652 - 0.889), and disease-free survival (DFS, HR = 0.686, 95% CI = 0.512 - 0.919)] than patients without ATM mutations. Subsequently, the verification results showed ATM mutations to be significantly correlated with longer OS in ICIs-treated patients (HR = 0.710, 95% CI = 0.544 - 0.928). Further exploration indicated ATM mutation to be significantly associated with regulated anti-tumor immunity (P &lt; 0.05). Conclusion: Our findings highlight the value of ATM mutation as a promising biomarker to predict ICIs therapy in multiple tumors.

Targeting STAT3 potentiates CDK4/6 inhibitors therapy in head and neck squamous cell carcinoma

Anti-CDK4/6 therapy has been employed for the treatment for head and neck squamous cell carcinoma (HNSCC) with CDK4/6 hyperactivation, but the response rate is relatively low. In this study, we first showed that CDK4 and CDK6 was over-expressed and conferred poor prognosis in HNSCC. Moreover, in RB-positive HNSCC, STAT3 signaling was activated induced by CDK4/6 inhibition and STAT3 promotes RB deficiency by upregulation of MYC. Thirdly, the combination of Stattic and CDK4/6 inhibitor results in striking anti-tumor effect in vitro and in Cal27 derived animal models. Additionally, phospho-STAT3 levels negatively correlates with RB expression and predicts poor prognosis in patients with HNSCC. Taken together, our findings suggest an unrecognized function of STAT3 confers to CDK4/6 inhibitors resistance and presenting a promising combination strategy for patients with HNSCC.

Frequent mutation of K-RAS in addition to BRAF V600E in Ameloblastoma – An immunohistochemical study

BackgroundAmeloblastoma is the most frequently encountered, enigmatic odontogenic tumor whose etiopathogenesis is still controversial. Understanding the pathogenic mechanism involved in Ameloblastoma and its proliferation aids in determining the best treatment option at an early stage. MAPK pathway are known to be active during tooth development, and also mutations in MAPK components have been identified in both benign and malignant tumors. The aim of this study was to evaluate the Immunohistochemical expression of biomarker BRAF V600E and K-RAS in Ameloblastoma and to examine if any, correlation exists between BRAF V600E and K-RAS expression. Methods30 formalin-fixed paraffin-embedded blocks of histopathologically diagnosed cases of Ameloblastoma were taken as samples. Immunohistochemistry using K-RAS and BRAF V600E antibody was performed and slides were evaluated both quantitatively and qualitatively using a quick score by an independent observer. ResultsK-RAS and BRAF V600E immunoexpression was evaluated and there is a significantly higher expression of K-RAS (mean score 6.20 ± 1.883) when compared with BRAF V600E (mean score 4.50 ± 2.271). BRAF V600E and K-RAS act independently in the pathogenesis of Ameloblastoma as the pattern of variation of BRAF V600E score was uneven when compared to K-RAS values. ConclusionOur data provide evidence that two independent mutation occurs in the same molecular pathway driving Ameloblastomas. But there is no correlation between K-RAS and BRAF V600E expression. Hence, combination therapy of K-RAS and BRAF V600E inhibitors can be helpful for the treatment of Ameloblastoma.

ALDH1A1 confers resistance to RAF/MEK inhibitors in melanoma cells by maintaining stemness phenotype and activating PI3K/AKT signaling

The mitogen-activated protein kinase (MAPK/ERK) pathway is pivotal in controlling the proliferation and survival of melanoma cells. Several mutations, including those in BRAF, exhibit an oncogenic effect leading to increased cellular proliferation. As a result, the combination therapy of a MEK inhibitor with a BRAF inhibitor demonstrated higher efficacy and lower toxicity than BRAF inhibitor alone. This combination has become the preferred standard of care for tumors driven by BRAF mutations.Aldehyde dehydrogenase 1A1 (ALDH1A1) is a known marker of stemness involved in drug resistance in several type of tumors, including melanoma. This study demonstrates that melanoma cells overexpressing ALDH1A1 displayed resistance to vemurafenib and trametinib through the activation of PI3K/AKT signaling instead of MAPK axis. Inhibition of PI3K/AKT signaling partially rescued sensitivity to the drugs. Consistently, pharmacological inhibition of ALDH1A1 activity downregulated the activation of AKT and partially recovered responsiveness to vemurafenib and trametinib. We propose ALDH1A1 as a new potential target for treating melanoma resistant to MAPK/ERK inhibitors.

Does patient sex affect the treatment outcome of immune checkpoint inhibitors? A Danish observational melanoma study

AimThe objective of this study was to evaluate whether patient biological sex influences treatment outcomes in patients with metastatic melanoma (MM) undergoing first-line immune checkpoint inhibitor (ICI) therapy. MethodsThe Danish Metastatic Melanoma Database (DAMMED) was employed to identify patients who underwent first-line ICI therapy for MM in Denmark from 2013 to 2021. Excluding adjuvant treatment, uveal and mucosal histological subtypes, the study conducted univariable and multivariable analyses to evaluate the influence of patient sex in survival analyses. Further, landmark survival of this real-world national cohort was described for progression free survival (PFS), overall survival (OS) and melanoma-specific survival (MSS). ResultsThe analysis encompassed a cohort of 1,378 patients with MM. Compared to male sex, females had significantly improved OS (p = 0.003) when tested in univariable testing. Multivariable analyses, controlling for age, performance status, lactate dehydrogenase level, BRAF status, M-stage, and number of metastatic sites revealed significant favourable outcomes associated with female sex irrespective of the considered survival metrics (pPFS = 0.014, pOS = 0.002, and pMSS = 0.03). The observed five-year OS rates of the entire cohort were 47% and 38%, while melanoma-specific survival were 50% and 45% for female and male, respectively. ConclusionIn this nationwide cohort of patients with MM undergoing first-line ICI treatment females exhibited superior treatment outcomes compared to males. Sex was identified as an independent predictive variable for treatment outcomes, irrespective of the chosen outcome measures considered. Our analyses are not able to conclude whether the differences in outcome is attributable to differences in biology or to treatment strategy.

A real world observational study characterizing patients with advanced prostate cancer treated with or without androgen receptor-pathway-inhibitor therapies in Alberta, Canada

BackgroundData are needed to improve the current understanding of clinical management and characteristics of patients with advanced prostate cancer (PC) treated with androgen receptor pathway inhibition (ARPI) therapy. MethodsThis retrospective cohort study using real-world, population-level data from Alberta, Canada included all individuals diagnosed in 2017-2020 with de novo metastatic castration-sensitive PC (mCSPC) or non-metastatic castration-resistant PC (nmCRPC) who initiated androgen deprivation therapy (ADT). For mCSPC, patients were classified as ARPI-exposed if they received an ARPI within 180 days of initiating ADT, while patients with nmCRPC were classified as ARPI-exposed if they received an ARPI within 2 years of diagnosis. ResultsThis study included 976 patients with mCSPC and 233 with nmCRPC of which 33.5% and 25.3% received an ARPI, respectively. The proportion of patients with mCSPC treated with an ARPI increased considerably for patients diagnosed in 2020 compared to 2017 (56.2% vs. 6.0%). In contrast, the use of ARPI to treat nmCRPC only increased marginally from 2017 to 2019/2020 (19.7% vs. 28.9%). Patients with mHSPC who were ARPI-exposed had longer median survival than patients who were ARPI-naive (38.47 (95% CI=32.84-NA). vs 34.19 (95% CI=33.33-38.83; p=0.03), with a higher proportion of patients surviving to 2-years. For nmCRPC, survival was similar between ARPI-exposed and ARPI-naive. In multivariable analyses, receiving ARPI for mCSPC was associated with younger patient age, more recent diagnoses, fewer comorbidities, a higher number of metastatic sites, referral to a medical oncologist as well as receiving surgery and radiation before ADT. Receiving ARPI for nmCRPC was associated with referral to a medical oncologist, younger age, and more recent diagnoses. ConclusionsOutcome analyses in this population suggest a continued unmet clinical need and complex clinical management pathways. Given that treatment pathways have evolved considerably, continued follow-up to understand the impact of these advancements on patient outcomes are warranted.

Methylation of the chromatin modifier KMT2D by SMYD2 contributes to therapeutic response in hormone-dependent breast cancer

Activating mutations in PIK3CA are frequently found in estrogen-receptor-positive (ER+) breast cancer, and the combination of the phosphatidylinositol 3-kinase (PI3K) inhibitor alpelisib with anti-ER inhibitors is approved for therapy. We have previously demonstrated that the PI3K pathway regulates ER activity through phosphorylation of the chromatin modifier KMT2D. Here, we discovered a methylation site on KMT2D, at K1330 directly adjacent to S1331, catalyzed by the lysine methyltransferase SMYD2. SMYD2 loss attenuates alpelisib-induced KMT2D chromatin binding and alpelisib-mediated changes in gene expression, including ER-dependent transcription. Knockdown or pharmacological inhibition of SMYD2 sensitizes breast cancer cells, patient-derived organoids, and tumors to PI3K/AKT inhibition and endocrine therapy in part through KMT2D K1330 methylation. Together, our findings uncover a regulatory crosstalk between post-translational modifications that fine-tunes KMT2D function at the chromatin. This provides a rationale for the use of SMYD2 inhibitors in combination with PI3Kα/AKT inhibitors in the treatment of ER+/PIK3CA mutant breast cancer.

Metastatic Merkel Cell Carcinoma After Simultaneous Pancreas-Kidney Transplantation: Fatal Outcomes.

Merkel cell carcinoma (MCC) is a rare, highly aggressive cutaneous malignancy. Immunosuppression increases the risk of MCC and is associated with poor prognosis. Organ transplant recipients (OTR) have worse overall survival (OS) than patients with immunosuppression due to other causes. Treating MCC after organ transplantation is challenging, as checkpoint inhibitor immunotherapy, the standard of care for treating MCC, increases the risk of transplant rejection. This paper reviews the cases of two simultaneous pancreas-kidney transplant (SPKT) recipients with MCC and explores the role of immunosuppression in the development of MCC. Immunosuppression was discontinued and checkpoint inhibitor therapy was initiated in the first patient and considered by the second patient. In both cases, treatment failed, and the patients died shortly after developing metastatic MCC. These cases illustrate the need for improved multidisciplinary treatment regimens for MCC in OTRs. J Drugs Dermatol. 2024;23(5):376-377.&nbsp; &nbsp; &nbsp;doi:10.36849/JDD.8234 &nbsp.

Phenotyping Hepatic Immune-Related Adverse Events in the Setting of Immune Checkpoint Inhibitor Therapy.

We present and validate a rule-based algorithm for the detection of moderate to severe liver-related immune-related adverse events (irAEs) in a real-world patient cohort. The algorithm can be applied to studies of irAEs in large data sets. We developed a set of criteria to define hepatic irAEs. The criteria include: the temporality of elevated laboratory measurements in the first 2-14 weeks of immune checkpoint inhibitor (ICI) treatment, steroid intervention within 2 weeks of the onset of elevated laboratory measurements, and intervention with a duration of at least 2 weeks. These criteria are based on the kinetics of patients who experienced moderate to severe hepatotoxicity (Common Terminology Criteria for Adverse Events grades 2-4). We applied these criteria to a retrospective cohort of 682 patients diagnosed with hepatocellular carcinoma and treated with ICI. All patients were required to have baseline laboratory measurements before and after the initiation of ICI. A set of 63 equally sampled patients were reviewed by two blinded, clinical adjudicators. Disagreements were reviewed and consensus was taken to be the ground truth. Of these, 25 patients with irAEs were identified, 16 were determined to be hepatic irAEs, 36 patients were nonadverse events, and two patients were of indeterminant status. Reviewers agreed in 44 of 63 patients, including 19 patients with irAEs (0.70 concordance, Fleiss' kappa: 0.43). By comparison, the algorithm achieved a sensitivity and specificity of identifying hepatic irAEs of 0.63 and 0.81, respectively, with a test efficiency (percent correctly classified) of 0.78 and outcome-weighted F1 score of 0.74. The algorithm achieves greater concordance with the ground truth than either individual clinical adjudicator for the detection of irAEs.

Evaluating the performance of optilite® C1Q and C2 turbidimetric assays in patients with complement deficiency or undergoing complement inhibitor therapy

Evaluating the performance of optilite® C1Q and C2 turbidimetric assays in patients with complement deficiency or undergoing complement inhibitor therapy

Oral decitabine/cedazuridine is an effective ambulatory therapy for patients with myelofibrosis refractory to JAK2 inhibitor therapy

MicroabstractPatients with myelofibrosis (MF) who are refractory to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers have dismal prognosis. We studied a novel ambulatory regimen of decitabine-cedazuridine (DEC-C) +/- JAKi therapy in patients with high-risk MF who were refractory to prior JAKi or MPN-accelerated phase. We demonstrate the therapeutic benefit of this strategy as evidenced by reduction or stabilization of blast cell counts, decrease in splenomegaly or successful bridge to stem-cell transplant. Myelosuppression is a common adverse event but treatment length reduction from 5 to 3 days of DEC-C/cycle is feasible and reduces toxicity without comprising the efficacy. BackgroundOutcomes are dismal for patients with myelofibrosis (MF) who are no longer responsive to JAK2 inhibitors (JAKi) and/or have increasing blast cell numbers. Although prior reports have suggested the benefits of intravenous decitabine (DAC) combined with ruxolitinib for patients with Myeloproliferative Neoplasm (MPN) accelerated/blast phase (AP/BP), decitabine-cedazuridine (DEC-C), an oral fixed-dose combination providing equivalent pharmacokinetic exposure, has not been evaluated in MF. MethodsWe conducted a retrospective analysis of 14 patients with high-risk MF refractory to ruxolitinib or MPN-AP (10-19% blasts) treated with DEC-C +/- JAKi at Mount Sinai Hospital from 2021-2024. ResultsThe cohort was elderly (median age,76 years) and almost uniformly possessed high risk mutations with 13 of the 14 patients progressing on JAKi therapy. With a median follow-up of 9.4 months, the median overall survival (OS) was 29 months for the entire cohort. Median OS was 10.8 months for MPN-AP and was not reached for ruxolitinib refractory MF patients. All patients (N=9) receiving >4 cycles of DEC-C had clinical benefit exemplified by a reduction in blast cell numbers, spleen size, and lack of progression to MPN-BP (78%). Furthermore, 3/14 patients proceeded to allogeneic stem cell transplant. Myelosuppression was a common adverse event which was managed by reducing the number of days of administration of DEC-C from 5 to 3. ConclusionsThis report demonstrates the feasibility, tolerability, and clinical benefit of an exclusively ambulatory regimen for high-risk, elderly patients with advanced MF which warrants further evaluation in a prospective clinical trial.