Discontinuation Of Therapy Research Articles

Abstract PO4-01-13: Effect of interruption or discontinuation of endocrine therapy on the prognosis of breast cancer patients: a cohort study using the real-world database

Abstract Background:Adjuvant endocrine therapy is the most important treatment modality as long as one, which can reduce the mortality risk and the recurrence risk for patients with hormone receptor-positive breast cancer. Currently, few studies has reported the association in poor adherence with overall survival(OS) or disease-free-survival(DFS). However, the use of prescription coverage in previous studies to describe patient adherence to endocrine therapy may not be representative of the patient's actual medication. Additionally, previous studies did not distinguish between interruption and discontinuation of endocrine therapy, which is different to clinician. This research used rigorous follow-up data and aims on the effects of discontinuation and interruption on patients with early-stage hormone receptor-positive breast cancer. Methods: Based on the Breast Cancer Information Management System (BCIMS), we identified patients diagnosed with stage I-III breast cancer with hormone receptor-positive and received endocrine therapy during January 1, 1990 to January 1, 2018 in West China Hospital (WCH), Sichuan University, China. Briefly, all patients diagnosed with breast cancer were included and prospectively followed from the diagnosis at WCH or the first visit to WCH for breast cancer. Information, including demographic characteristics, medical history, laboratory results, pathological information, treatments and clinical outcomes, were obtained from clinical records and interviews. Kaplan-Meier analysis, Time-Dependent Cox Regression Model, and subgroup analysis were performed to evaluate the effectiveness of interruption or discontinuation of endocrine therapy. And “X-tile” software is used to select cutoff values in survivorship data. Results:A total of 3,418 eligible patients were included with 8.13(±1.96) years median follow-up. Of these patients, 19.5% did not adhere to standard endocrine regimens, with 6.9% discontinuing and 12.7% discontinuing. The multivariate cox analysis indicates that discontinuation group (DFS:HR=9.71, [95%CI]5.21-18.34,P <0.001; OS:HR=10.41, [95%CI]5.63-19.24,P <0.001) increased the risk of death and breast cancer events compared to the adherence group, but not shown statistical significance difference in the interruption (DFS:HR=1.03,[95%CI]0.23-4.66, P =0.975; OS:HR=1.17, [95%CI]0.26-5.28,P =0.840). We further analyzed the interruption and discontinuation group respectively. In the interruption group, we found cutoff value with 30 months in survival risks but didn't find statistical significance difference in DFS and OS compared to the adherence groups. For the discontinuation group, we divided the patients into low-risk and high-risk groups according to cutoff value (23 months), the final results showed that the high-risk group who took the endocrine therapy less than 23 months had increased the rate of OS(HR=23.98,[95%CI]11.71-49.14, P< 0.001) and DFS(HR=24.03,[95%CI]11.51-50.18, P< 0.001). Conclusion:This study found that interruption of endocrine therapy may not affect prognosis of HR+ breast cancer patients, but prolonged discontinuation increases the risk of relapse and death. Therefore, clinicians should educate patients taking endocrine therapy and encourage those who discontinue the drug to take the drug again as soon as possible. A.Kaplan-Meier Curve for OS B.A.Kaplan-Meier Curve for DFS Kaplan-Meier Curve for OS and DFS in the Interruption Group according to the events location Kaplan-Meier Curve for OS and DFS in the Discontinuation Group according to the total duration of medication Citation Format: Ya Huang, Jie Chen, Yunhao Wu. Effect of interruption or discontinuation of endocrine therapy on the prognosis of breast cancer patients: a cohort study using the real-world database [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 PO4-01-13.

Abstract PO4-11-01: Validation of a CARG-BC-based score for the prediction of therapy-induced toxicities in patients with metastatic breast cancer

Abstract Introduction Prediction of treatment-induced toxicities is important in order to tailor and adjust oncologic therapies. As limited tools exist to predict the risk of therapy-induced toxicities in patients with metastatic cancer, we aimed to develop and to validate a score for the prediction of therapy-induced toxicities in patients with metastatic breast cancer treated with chemotherapy and immunotherapy. The score was based on the Cancer and Aging Research Group-Breast Cancer early-stage breast cancer score for prediction of chemotherapy-induced toxicities. Methods All patients treated for metastatic breast cancer with chemotherapy and immunotherapy at the Department of Gynecology, Obstetrics and Reproductive Medicine at Saarland University Hospital between 01/2014 and 05/2022 were included in this retrospective study. Patient characteristics and therapy-relevant oncological parameters were recorded, as well as therapy-induced toxicities (recorded according to CTC), hospitalization rates, toxicity-related dose reductions and therapy discontinuations. In the first cohort (development cohort), a new score for the prediction of therapy-induced toxicities was developed using ROC analysis and multivariate analysis based on the CARG-BC score. In the second cohort (validation cohort), this was validated using Pearson’s correlation coefficient. Results Data from 32 patients were analyzed for the development cohort, and inclusion of 102 patients contributed to the validation cohort. The newly developed score consists of seven independent factors for the prediction of toxicities ≥ CTC III° and includes the parameters “presence of visceral metastases” (yes/no), “received previous lines of therapy” (yes/no), “limited mobility/able to walk less than one kilometer” (yes/no), “a fall in the last six months” (yes/no), “social interactions” (yes/no), “pretherapeutic change of transaminases” (yes/no) and “pretherapeutic change of hemoglobin” (hemoglobin </> 10 g/dl). Based on the results, three risk groups were defined (low (0-2), medium (3-5) and high (6-15) risk). 28% of patients were in the low-risk group, 37% in the intermediate-risk group and 34% in the high-risk group. Overall, 49% of the patients had toxicities ≥ CTC III°. Distributed across the subgroups, these occurred in 14% in the low-risk group, 34% in the intermediate-risk group and in 52% in the high-risk group (p ≤ 0.01). Risk score results showed a correlation with treatment discontinuation and hospitalization rate (p ≤ 0.01), but not with dose reduction (p = 0.77). Conclusion The available data show a correlation between the risk score results and the occurrence of systemic therapy-induced toxicities in patients with metastatic breast cancer. The results can be used to further identify risk populations and to systematically apply preventive and supportive measures in order to approve quality of life in patients with metastatic breast cancer. Citation Format: Julia SM Zimmermann, Aylin Aygün, Askin Kaya, Marc P Radosa, Christoph G Radosa, Erich F Solomayer, Julia C Radosa. Validation of a CARG-BC-based score for the prediction of therapy-induced toxicities in patients with metastatic breast cancer [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 PO4-11-01.

Abstract PO1-28-08: The Efficacy and Safety Results of Neoadjuvant Phase II study of Anlotinib plus Sintilimab Combined with Chemotherapy in Triple-negative Breast Cancer (NeoSACT)

Abstract Background: In triple-negative breast cancer (TNBC), the co-administration of programmed mortality 1 (PD-1) inhibitors and chemotherapy has demonstrated enhanced pathological complete response (pCR) rates and improved event-free survival (EFS). Previous research has suggested that antiangiogenic agents possess the ability to normalize aberrant tumor vasculature, thereby converting the immune-suppressive tumor microenvironment into an immune-supportive one. This study aims to assess the effectiveness and safety of combining the neoadjuvant small-molecule antiangiogenic drug Antilotinib with the PD-1 inhibitor Sintilimab and chemotherapy. Methods: In this study, a single-arm, open-label, phase II trial was conducted to evaluate the effectiveness of Anlotinib plus Sintilimab, in conjunction with nab-paclitaxel and carboplatin, followed by epirubicin and cyclophosphamide, in eligible patients with stage II-III TNBC. The treatment regimen consisted of four cycles of nab-paclitaxel (100 mg/m² on day 1, 8 and 15) plus carboplatin (AUC 5) every 21 days, followed by four cycles of epirubicin (90 mg/m2) plus cyclophosphamide (600 mg/m2) every 21 days. Additionally, patients received Sintilimab (200mg) every 21 days and Antilotinib (12mg, po on day 1-14, every 21 days) for eight cycles. Patient enrollment was conducted according to a Simon two-stage design. The primary endpoint was the rate of pCR based on the definition of ypT0/Tis ypN0. Secondary endpoints included residual cancer burden (RCB), EFS, overall survival (OS), adverse events (AE), and immune response biomarkers. Results: Between September 2021 and August 2023, a cohort of 31 patients was enrolled, with a median age of 48 years (range: 30-70 years). Among the participants, 21 out of 31 (67.8%) presented with clinical stage II disease, 23 out of 31 (74.2%) had T2 tumors, and 19 out of 31 (61.3%) exhibited clinically positive lymph nodes. In the initial phase of the study, a total of 11 patients were evaluated, out of which 7 patients achieved a pathological complete response (pCR) after surgery. Consequently, 20 patients were included in the subsequent stage, and among the 19 patients who were evaluable, 13 achieved pCR. One participant withdrew from the study prematurely following the third cycle due to grade 3 liver impairment, resulting in the discontinuation of study therapy as well as subsequent surgery. In the intention-to-treat (ITT) population, the overall pCR rate was determined to be 64.5% (20/31, 95% CI 45.4% - 80.8%). Additionally, 80.6% (25/31, 95%CI 62.5% - 92.5%) of the patients were assessed as having a RCB score of 0 or 1. A total of 31 patients were subjected to adverse event assessment. Among them, 12 patients (38.7%) experienced one or more grade 3/4 adverse events (AEs) according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The grade 3/4 AEs encompassed rash (7 patients, 22.6%), anemia (4 patients, 12.9%), thrombocytopenia (3 patients, 9.7%), neutropenia (2 patients, 6.4%), leukopenia (2 patients, 6.4%), hypothyroidism (2 patients, 6.4%), and elevated AST/ALT (1 patient, 3.2%). Conclusions: The neoadjuvant regimen comprising the combination of Anlotinib and Sintilimab alongside chemotherapy demonstrated a pCR rate of 64.5%, with no observed emergence of novel toxicity signals. Ongoing investigations encompass biomarker assessments and survival analyses. Pertinent clinical trial details can be found under the identifier NCT04877821. Citation Format: Liulu Zhang, Mei Yang, Ciqiu Yang, Teng Zhu, Hong-Fei Gao, Kun Wang. The Efficacy and Safety Results of Neoadjuvant Phase II study of Anlotinib plus Sintilimab Combined with Chemotherapy in Triple-negative Breast Cancer (NeoSACT) [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 PO1-28-08.

Abstract PO5-06-02: Phase II Trial of Combination of Atezolizumab, Cobimetinib and Eribulin (ACE) or Atezolizumab and Eribulin (AE) in patients with metastatic inflammatory breast cancer (IBC): Clinical data of both cohorts

Abstract Background: Metastatic IBC is an unmet clinical need due to the aggressiveness of this breast cancer subtype. Gene expression analysis of IBC samples post-neoadjuvant chemotherapy has revealed that dysregulation of immune pathways is common in tumors that do not have a complete pathologic response (pCR) to chemotherapy. The immune checkpoint PD-L1 is expressed in a third of IBC cases, and the MEK inhibitor, cobimetinib, has been shown to enhance the expression of PD-L1, the target of atezolizumab. Taken together, dual targeted therapy with atezolizumab and cobimetinib is hypothesized to be synergistic. Eribulin is a standard of care chemotherapy used in patients who have progressed on anthracycline-taxane based regimens. Materials and Methods: Patients received triple or double combination therapy depending on the timing of their enrollment. Patients with metastatic IBC who had measurable disease after at least 1 standard regimen were eligible. Any receptor subtype was allowed, and PD-L1 positivity was not required. The study began with a single cohort (n=17 patients) receiving all 3 agents with a lead-in phase to determine the MTD of cobimetinib in this setting. The study was later amended to include only atezolizumab and eribulin (cohort 2). Ten patients were treated in cohort 2. The study closed early due to lack of efficacy in cohort 2 and the changing landscape of metastatic breast cancer therapies. In cohort 1, atezolizumab was given every 2 weeks (840 mg), cobimetinib was given at 60/40/20 mg once daily, and eribulin was given at 1.4mg/m2 on day 1 and day 8 of 21-day cycles. In cohort 2, atezolizumab was given every 3 weeks (1200 mg) during the PD window and cycles 1-4, and then every 4 weeks (1680 mg) during maintenance, and eribulin was given at 1.4mg/m2 on day 1 and day 8 of 21-day cycles. Results: The MTD of cobimetinib was 40mg. In cohort 1, 17 patients were treated, 14 had at least 1 restaging evaluation. Seven patients had a partial response (50%) and 3 stable disease. The cohort was predominantly triple receptor-negative (n=13/17), with a median age of 51 yrs. The median PFS for patients in cohort 1 was 6.2 months (0-54.1). There were 2 exceptional responders, both with triple negative subtype, one of whom remains on therapy for >4.5 years without evidence of disease. The median overall survival was 29.6 months (2.9-133). The AE profile was largely expected, with 3 irAEs (1 grade 5 colitis, and 2 grade 2 pneumonitis), and one other patient with cardiac dysfunction requiring discontinuation of cobimetinib and atezolizumab. The MTD of cobimetinib was 40 mg. Cobimetinib-related toxicities were mild and largely gastrointestinal tract related. In cohort 2, only 1 patient experienced PR, and the median PFS was 3 months (1.2-6.2) and overall survival 8.3 months (1.8-19.9). One patient experienced autoimmune related hepatitis requiring discontinuation of protocol therapy. Due to excesive myelosuppression, dose of erublin was reduced to 1.1 mg per meter squared on day 1 and 8 and pegfilgastrim was added on day 9< Conclusions: The response profile of the triple combination demonstrated promise, and suggests that MEK inhibition may warrant further investigation as a strategy in metastatic IBC in a larger sample size. However, there does not appear to be synergy between atezolizumab and eribulin without the addition of targeted therapy. Citation Format: Angela Alexander, Hope Murphy, James Reuben, H. T. Carisa Le-Petross, Deanna Lane, Monica Huang, Savitri Krishnamurthy, Yun Gong, Dan Gombos, Nimisha Patel, Richard Allen, Suyu Liu, Anisha Patel, Andrew Futreal, Ignacio Wistuba, Rachel Layman, Naoto Ueno, Debu Tripathy, Bora Lim, Vicente Valero. Phase II Trial of Combination of Atezolizumab, Cobimetinib and Eribulin (ACE) or Atezolizumab and Eribulin (AE) in patients with metastatic inflammatory breast cancer (IBC): Clinical data of both cohorts [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 PO5-06-02.

Abstract PO2-11-03: A long-term follow-up of patients who interrupted endocrine therapy to become pregnant following breast cancer surgery

Abstract Introduction: Regarding discontinue adjuvant endocrine therapy to attempt pregnancy, Pregnancy Outcome and Safety of Interrupting Therapy for Women with Endocrine Responsive Breast Cancer (POSITIVE) clinical trials have revealed temporary interruption of endocrine therapy to attempt pregnancy did not confer short-term risk of breast cancer events. However, that report involved a short observation period, longer-term follow-up is required. This study was aimed to evaluate the safety of endocrine therapy interruption with long-term followed-up data base. Methods: This was a retrospective study using surveying of medical chart data between June 2007 and November 2015 at St. Luke’s International Hospital. The subjects were 65 patients with estrogen-receptor positive primary breast cancer (clinical stage I-III) who had been performed fertility preservation prior to starting breast cancer treatment. Adjuvant endocrine therapy completion was defined as 120 months (10 years) and discontinuation was defined as < 120 months. Using the definition, we classified the patients into an endocrine therapy interruption-group and a continuation-group. The primary outcome was the breast cancer free interval (BCFI). We defined breast cancer events as local, regional, or distant recurrence of invasive breast cancer or new contralateral invasive breast cancer during follow-up. Results: Median follow-up period was 110 (range, 36–181) months. The number of adjuvant endocrine therapy interruption-group was 30 and continuation-group was 35. Among 65 patient, the mean patient age in the interruption vs. continuation groups were as follows: 38(range, 26-48) years vs. 36.5 (range, 26–45) years at breast cancer diagnosis and HER2 positive breast cancer was identified in 4 (11.4%) vs 4 (13.3%) patients. Clinical stages were Stage I, 9 (30%) vs. 11 (31.4%) patients; Stage II, 18 (60%) vs. 18 (51.4%) patients; and Stage III, 3 (10%) vs. 6 (17.1%) patients. Chemotherapy was administered in 17 (56.7%) and 23 (65.7%) patients, respectively. The median duration of endocrine therapy before interruption was 25.5 months: 3 (10%) patients received endocrine therapy for 0–18 months, 16 (53.3%) for 18–30 months, and 11 (36.7%) for >30 months. The BCFI was 124 and 119 months in the interruption and continuation groups, respectively (p = 0.16). There were 6 (20%) and 9 (25.7%) breast cancer events in the interruption-group and continuation-group, respectively (p = 0.4). All the pregnancies were in the endocrine therapy interruption group (17 pregnancies, 16 deliveries), with one pregnancy involving the delivery of twins. Three pregnancies were spontaneous. Endocrine therapy was resumed in 16 (59.3%) patients in the interruption-group (median time to resumption, 20.5 months). One patient developed distant metastasis during endocrine therapy interruption period. Conclusion: Among patients who performed fertility preservation prior to starting breast cancer treatment, our long-term follow-up data, almost 9 years, suggested that the BCFI was not statistically different between endocrine therapy interruption-group and continuation-group. A limitation of this study is that only three cases of Stage III breast cancer were included in the interruption group. Therefore, we consider that careful decisions should be made regarding interruption of endocrine therapy. Citation Format: Risa Kasahara, Atsuko Kitano, Fumi Akitani, Kyoko Shiota, Kumiko Kida, Junko Takei, Atsushi Yoshida. A long-term follow-up of patients who interrupted endocrine therapy to become pregnant following breast cancer surgery [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 PO2-11-03.

Abstract PO1-06-14: Preliminary results of a phase I dose escalation study of eribulin in combination with copanlisib in patients with metastatic triple negative breast cancer (TNBC)

Abstract Background: Aberrant PI3K pathway signaling is frequently observed in TNBC. Increasing evidence indicate that PI3K pathway activation maintains the stemness and chemoresistance of breast cancer stem cells (CSCs). PI3K inhibition sensitizes CSCs to chemotherapy. Eribulin (E), a non-taxane microtubule dynamics inhibitor, showed overall survival benefit in metastatic HER2 negative BC. Preclinically, the addition of copanlisib (C), a potent pan-class I PI3K inhibitor that is highly selective against α and δ PI3K isoforms, improved anti-tumor effect in both E-sensitive and resistant TNBC patient-derived xenograft models, irrespective of PIK3CA/PTEN alteration status. Here we report the preliminary data of the phase I dose escalation trial of E+C in patients with metastatic TNBC. Methods: This trial includes a phase I study to determine the dose limiting toxicity (DLT) and recommended phase 2 dose (RP2D) of E+C, followed by a randomized phase II study of E+C (at RP2D) versus E (stratified by tumor PIK3CA/PTEN mutation status) with progression-free survival (PFS) as the primary endpoint. Key eligibility included patients with: metastatic TNBC who progressed on ≤5 lines of chemotherapy, prior anthracycline/taxane chemotherapy (unless contraindicated), ECOG 0-1, adequate organ function and known tumor PIK3CA/PTEN/AKT mutation status. Key exclusions include: prior receipt of E or any PI3K/mTOR/AKT inhibitor, grade ≥2 neuropathy, presence of tumor AKT mutation, and uncontrolled diabetes, hypertension or congenital QT prolongation. A 3+3 design was used to determine the DLT and RP2D. Dose level 1 (DL1) started with E at 1.1 mg/m2 mg IV and C at 45 mg IV on days (D) 1/8 of 21-D cycle, with the potential to escalate to 2 additional dose levels – DL2: E 1.4 mg/m2 and C 45 mg on D 1/8; DL3: E 1.4 mg/m2 and C 60 mg on D 1/8. Results: Eight patients were enrolled in the phase I study and received at least 1 dose of E+C. The median age was 48.5 (range, 26-67) years. The majority of patients identified as White (additionally 2 Hispanic, 1 Black) and had an ECOG performance status of 1 (n=6, 75.0%). Tumor PIK3CA and PTEN alterations were each observed in 1 patient. Median number of cycles received were 2 (range, 1-5). All 8 patients had at least 1 treatment-related adverse event (TRAE). The most common TRAEs across all dose levels were: lymphopenia (n=5, 62.5%), neutropenia (n=5, 62.5%), hyperglycemia (n=4, 50.0%), anemia (n=4, 50.0%) and fatigue (n=4, 50.0%); most toxicities were grade (G) 1-2. G3 hyperglycemia and hypertension were observed in 1 patient each, were medically managed and did not lead to treatment interruption. 1 patient was diagnosed with pulmonary embolism, possibly attributed to study therapy and breast cancer. DLTs were reported in 2 of 2 patients treated at DL2 - 1 patient developed G3 rash responsive to oral corticosteroids, and 1 patient developed G3 acute kidney injury in the setting of hypovolemia and discontinued study therapy. No additional patients were enrolled in DL2. No DLTs were observed in all 6 patients treated at DL1. 1 patient treated at DL1 had possible G1 non-infectious pneumonitis that resolved spontaneously on short interval imaging. Stable disease was observed in 2 of 6 response-evaluable patients (33.3%). 1 patient achieved regression of cutaneous disease following 1 cycle of therapy as assessed by the treating investigator. DL1, E at 1.1 mg/m2 plus C at 45 mg IV, was determined to be the RP2D. Tumor tissue biomarker analysis is underway. Conclusion: These data indicate that E+C at DL1 is a well-tolerated regimen warranting further investigation. The study is actively enrolling patients to the phase II study. Clinical trial information: NCT04345913. Funding Source: National Cancer Institute. Citation Format: Nusayba Bagegni, Brittney Haas, Leslie Nehring, Jingqin Luo, Laura Kennedy, Meghna Trivedi, Manali Bhave, Rabih Said, Cynthia Ma. Preliminary results of a phase I dose escalation study of eribulin in combination with copanlisib in patients with metastatic triple negative breast cancer (TNBC) [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 PO1-06-14.

Abstract PO5-21-10: Efficacy and Safety of Alpelisib in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor: An Open-label, Multi-centre, Prospective, Single Arm Clinical Trial

Abstract Introduction: Currently, patients with luminal metastatic breast cancer receive a CDK4/6 inhibitor in combination with endocrine therapy as a first or second line of treatment. When tumors become resistant to the CDK4/6 inhibitors, treatment with alpelisib (PI3K inhibitor) in combination with an endocrine agent can be a next treatment option if an activating PIK3CA mutation is confirmed (cfr. SOLAR-1 trial). However, limited data is available after treatment with CDK4/6 inhibitors (cfr. BYLieve trial) and even less about alpelisib in later lines of therapy. Therefore, we aim to investigate the therapeutic efficacy and safety of alpelisib in combination with an endocrine agent in PIK3CA-mutated advanced breast cancer patients in later lines after prior CDK4/6i treatment. Methods: This is an open-label, prospective, multi-centre, single arm clinical trial enrolling patients from both the University Hospital of Leuven (UHL) and Ghent University Hospital (GUH). For each patient, metastatic tumor was tested for PIK3CA mutations using the UHL 96 gene panel. Our endpoints are clinical benefit rate, progression-free survival, time to treatment discontinuation (defined as the date of starting alpelisib to the date of treatment discontinuation or death) and safety. Descriptive statistics were used. Results: Between June 18th 2019 and August 23rd 2021, 38 patients have been included with confirmed PIK3CA hotspot mutations. All patients had CDK4/6 inhibitor in an earlier treatment line. Median age at alpelisib initiation was 64 years (range: 39-82 years). Included patients had a median of four lines of systemic therapy for advanced disease prior to starting alpelisib (range: 1- 11). Clinical benefit rate (patients receiving ³ 6 months of treatment) was 26.3% (10/38). The median progression-free-survival as well as time to treatment discontinuation were 3 months (range: 1 – 18). Dose reduction due to toxicity occurred in 11 patients (29%), of which 7 due to hyperglycemia grade 3, 2 due to diarrhea grade 3, 1 due to rash grade 2 and 1 due to anorexia. Finally, 84% of patients (32/38) stopped alpelisib treatment because of progressive disease, 8% (3/38) because of intolerance, one patient died because of cerebral hemorrhage during treatment, one patient withdrew their informed consent and one patient is still ongoing with the treatment. Conclusion: Our trial demonstrates activity of alpelisib in patients with PIK3CA mutated advanced breast cancer in later lines of treatment after treatment with CDK4/6 inhibitors with a clinical benefit rate of 26.3%. Discontinuation of therapy due to toxicity was seen in only 8% of patients, although toxicity induced dose reduction was needed in 29% of patients. These findings support the results of the BYLieve trial and additionally show efficacy of alpelisib in later lines of treatment for hormone receptor-positive advanced breast cancer. Citation Format: Rik Van Severen, Anne-Sofie De Crem, Hava Izci, Laurence Slembrouck, Isabelle Vanden Bempt, Hans Wildiers, Kevin Punie, Eline Naert, Ingeborg Hilderson, Ann Smeets, Ines Nevelsteen, Anne Deblander, Nynke Willers, Patrick Berteloot, Ignace Vergote, Sileny Han, Adriaan Vanderstichele, Giuseppe Floris, Christine Desmedt, Hannelore Denys, Patrick Neven. Efficacy and Safety of Alpelisib in PIK3CA-mutated, hormone receptor-positive advanced breast cancer after a CDK4/6 inhibitor: An Open-label, Multi-centre, Prospective, Single Arm Clinical 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 PO5-21-10.

Abstract PO2-11-05: Pregnancy Trends Following Breast Cancer Treatment: Insights from a Large Single-Center Experience

Abstract Background The treatment of breast cancer (BC), particularly chemotherapy and long-term endocrine therapy (ETx), can have an impact on fertility which young women with BC have concerns about. This study was therefore conducted with the objective of providing comprehensive real-world data on pregnancy following BC treatment, aiming to shed light on this crucial aspect of survivorship and potentially guide clinical practice and patient counseling. Methods A retrospective analysis was conducted using medical records of women aged 18-40 years diagnosed with BC at a single tertiary medical center between December 2010 and September 2020. The pregnancy rate and timing in relation to characteristics and treatment were analyzed, along with the outcomes of discontinuing ETx for the purpose of pregnancy. Statistical analyses including Kaplan-Meier curves and Cox regression were performed. Results The study included 995 patients, with a mean age at diagnosis of 31.5 years. Of these, 115 (11.6%) patients became pregnant after BC treatment. Patients with a prior history of pregnancy had a lower likelihood of conception post-treatment (HR=0.39, 95% CI: 0.24-0.67, P< 0.001). Women with hormone receptor positive BC was also associated with lower pregnancy rates than with hormone receptor negative BC (HR=0.52, 95% CI: 0.36-0.77, P=0.001). Age at diagnosis and chemotherapy did not significantly impact pregnancy rates (P=0.251 and P=0.140, respectively). Among 662 women with hormone receptor positive BC, there were 76 (11.5%) women who discontinued ETx for the purpose of pregnancy and 69.7% (53 out of 76) achieved pregnancies. The median duration of medication before cessation among these women was 26.5 months and the duration of ETx did not significantly affect pregnancy rates (P=0.204). Recurrence after discontinuation of ETx for pregnancy was observed in 17% (13 out of 76) of cases. The median breast cancer-free interval among these cohort was 71 months. Late recurrence, occurring after 5 years of treatment, was observed in 77% (10 out of 13) of cases. Among the patients who experienced recurrence, 62% (8 out of 13) were loco-regional, while 38% (5 out of 13) were distant recurrences and the success rate of achieving pregnancy was 69% (9 out of 13), while 31% (4 out of 13) did not get pregnant. Conclusion This study provided real-world data regarding the influence and outcomes of ETx on pregnancy in young BC survivors. The discontinuation of ETx for the purpose of pregnancy appears to result in successful conception. Recurrence rates after therapy discontinuation for pregnancy were observed in a subset of cases, with late and loco-regional recurrences being more common. Results of uni- and multi-variable cox proportional hazards model evaluating time to pregnancy * The pregnancy rate was calculated using Kaplan-Meier (KM) estimates. Pregnancy rate according to ETx and its discontinuation Pregnancy rate according to duration of ETx prior to Discontinuation for pregnancy * The p-value was calculated using Chi-square analysis Citation Format: Young-jin Lee, Tae-Kyung Yoo, Sae Byul Lee, Jisun Kim, Il-Yong Chung, Beom Seok Ko, Jong Won Lee, Byung Ho Son, Hee Jeong Kim, Jeonghee Ahn, Seonok Kim. Pregnancy Trends Following Breast Cancer Treatment: Insights from a Large Single-Center Experience [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 PO2-11-05.

Abstract PO5-12-07: Analyzing Patient Experiences with Adjuvant Hormone Therapy for Early Breast Cancer Treatment via NLP/ML on Social Media: Symptoms and Their Mitigation

Abstract Understanding the early breast cancer (eBC) patient experience of disease and treatment is critical to addressing unmet patient needs, improving outcomes, and informing the next wave of drug development. Traditional approaches, such as interviews or focus group studies, are resource intensive and have limitations in reflecting the diverse experiences of patients with different disease characteristics, treatments, and sociodemographic backgrounds, and in detecting rare severe events that could potentially lead to therapy discontinuation. To overcome these limitations, we have developed a semi-automated approach utilizing Natural Language Processing (NLP) and Machine Learning (ML) methods in application to public patient forums to extract patient insights. Specifically, we analyzed 500,000 anonymized posts from the BreastCancer.org forum, utilizing Transformer-based methods to identify posts related to eBC patient experiences treated with standard hormonal therapies (HT). First, a novel ML-based model identified posts related to eBC adjuvant HT. For those, patient demographics, symptoms and their severity, and symptom management strategies such as exercise and yoga were subject to further analysis. Out of 362,074 relevant eBC posts, 32 symptoms and 9 impacts were significantly associated with at least one of the six hormonal therapies we considered. Hot flushes (relative risk [RR]: 6.70; 95% CI: 3.36–13.36), arthralgia (RR: 6.67; 95% CI: 3.53–12.59), weight increase (RR: 4.83; 95% CI: 3.20–7.28), mood swings (RR: 7.36; 95% CI: 5.75–9.42), insomnia (RR: 4.76; 95% CI: 3.14–7.22), and depression (RR: 3.05; 95% CI: 1.71–5.44) demonstrated the strongest associations. Severe headache, dizziness, back pain, and muscle spasms showed significant associations with ≥1 HT despite their low overall prevalence in eBC posts. Notably, posts contained a wide range of symptoms severity, including rarely seen symptoms in smaller patient pools, such as severe night hot flashes leading to treatment discontinuation. Symptoms/impacts mentioned in association with exercise and yoga as a way for symptom mitigation included hot flashes, arthralgia, fatigue, anxiety, depression, and pain. Of those posts, 53.3% to 82.5% reported positive or neutral sentiments for exercise, and 22.2% to 100.0% for yoga. For posts specifically mentioning the management of side effects of HT, between 50.0% and 63.5% had a positive sentiment associated with exercise concerning each of the symptoms/impacts with a lower positive impact related to yoga (between 11.1% and 43.0% of posts). Posts discussing pain management and exercise included a higher proportion of negative feedback, versus positive sentiment for depression. Posts related to yoga as an HT symptom mitigation strategy had a higher prevalence of negative sentiments for anxiety and depression. Our proposed ML/NLP-based approach to collecting patient feedback from publicly available forums complements standard qualitative methods by enabling the scalable extraction of insights from hundreds of thousands of online conversations that could span a broad diversity of symptoms and well-being reflections. Furthermore, our findings suggest the potential value of informing clinical outcome assessment (COA) measurement for clinical trials, alone and in combination with standard qualitative research approaches to guide the next clinical development. Overall, our study highlights the significant potential of NLP and ML to address the critical need to better understand the eBC patient experience of disease and treatment to improve outcomes for patients. Citation Format: Sameet Sreenivasan, Chao Fang, Emuella Flood, Natasha Markuzon, Jasmine Sze. Analyzing Patient Experiences with Adjuvant Hormone Therapy for Early Breast Cancer Treatment via NLP/ML on Social Media: Symptoms and Their Mitigation [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 PO5-12-07.

Abstract PO2-17-05: Pharmacy fills but not baseline distress or other clinical factors can identify those at high risk for early adjuvant endocrine therapy discontinuation

Abstract Background Completion of the recommended 5-10 year course of adjuvant endocrine therapy (AET) course is low, and few risk factors for discontinuation have been identified. We examined factors associated with early AET discontinuation in a large cohort with patient-reported outcomes (PROs) and other measures routinely used in clinical care at four sites within an academic health system's multidisciplinary cancer center. Methods We examined postmenopausal women with stage I-III hormone-receptor positive breast cancer identified using the registry at an academic multidisciplinary cancer center 2014-19 who received a prescription for AET, and followed them for up to 5 years. Breast cancer extent of disease and treatments, Elixhauser comorbidity index, medication number and sociodemographic characteristics (age, race/ethnicity, insurance, area deprivation index of zip code of residence) were abstracted from the electronic health record (EHR). PRO measures included the Distress Thermometer (DT, scored 0-10) and its associated problem list (39 yes/no questions), and the Patient Health Questionnaire-9 (depression), all administered routinely as part of clinical care between diagnosis date and start of AET. If >1 PRO performed during that time, the measure closest to AET start was used. DT was dichotomized using the clinically accepted score of 4 as the threshold for severe distress, as was Patient Health Questionnaire-9 (PHQ-9) depression ( >5). AET prescription information included both prescription date from the EHR, and prescription fills assessed using an all-payer pharmacy data source. AET was defined as discontinued (d/c) when no prescription had been filled at any pharmacy for at least 90 days. We used nonparametric hypotheses test for two-samples (d/c vs. no d/c) as well as Kaplan-Meier product-limit time-to-event analyses with censoring for recurrence, death, or change of provider, and advanced machine learning to examine the association of these variables with discontinuation prior to five years. 54 curated covariates were examined in all, corresponding to a Bonferroni statistical significance p-value threshold of 0.001 to control type I error. Sensitivity analyses were performed to 1)use alternative date of DT (closest to diagnosis date) and 2)to examine d/c defined as 180 days. Results Among the cohort of 985 women (74% stage I, 25% Elixhauser comorbidity score >2), 36.9% had a DT >4, and 6.7% a PHQ-9 >5. The cohort had a median followup time of 954 days, and during followup 291 women ( 29.5) % discontinued before completion of the 5-year course or censoring for death, change to a provider outside the system or study end date in 2021. Over 40% of women who stopped filling prescriptions never had their prescriptions discontinued by their physician in the EHR. None of the examined variables including those for Distress and PL, PHQ-9 and measures of extent of disease, cancer treatments, medication number and sociodemographic characteristics were associated with early discontinuation. Results were similar in analyses using the DT date closest to diagnosis or a 180-day prescription fill gap. We also used advanced machine learning with respect to time to event discontinuation had similar results. Conclusions. Clinically available EHR data including two PRO measures were not reliable predictors of early discontinuation. However, many women who had discontinued still had orders for AET in the EHR, suggesting that their physicians were unaware that they had stopped filling prescriptions. Future work should examine whether routine monitoring of prescription fills might be enlisted to identify these women and assist with education, supportive care or other assistance to restart. Citation Format: Joan Neuner, Rodney Sparapani, Jacob Tiegs, Vaia Makris, Melinda Stolley, Sailaja Kamaraju, Bradley Crotty, Kathryn Flynn. Pharmacy fills but not baseline distress or other clinical factors can identify those at high risk for early adjuvant endocrine therapy discontinuation [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 PO2-17-05.

Abstract PO3-17-10: Real-World evidence for Pembrolizumab-based neoadjuvant chemotherapy in early-stage triple negative breast cancer: a single institution experience

Abstract Introduction The improved pathologic complete response (pCR) and event-free survival observed in Keynote-522 trial (NCT03036488) led to the adoption of (neo)adjuvant pembrolizumab (pembro)-based chemotherapy (CT) for high-risk early-stage triple-negative breast cancer (eTNBC) in various jurisdictions. However, Real-World Evidence (RWE) for (neo)adjuvant pembro in this setting would further support its ongoing funding and utilization. The aim of this study was to provide RWE for (neo)adjuvant pembro in eTNBC in the United Arab Emirates (UAE), where patients often present with more-advanced disease stages and poorer prognostic profiles compared with North America and Europe. Method This is a retrospective cohort study involving all patients treated with pembro-based neoadjuvant chemotherapy (NACT) for eTNBC at a major cancer center (Tawam Hospital) in the UAE between October 2021 and June 2023. Patient characteristics, clinicopathologic features, immune related adverse events (irAE) and disease outcomes were reported by descriptive statistics. An exploratory analysis was also conducted to examine the associations between pCR and HER-2 status (HER2 negative vs HER2 low) as well pCR and treatment interruption (< vs = > 2 weeks). ResultA total of 41 patients, with a median age of 44 years, were included in this study. All had an ECOG status of 0-1. The clinical and pathological characteristics are provided in Table 1. Pathogenic germline BRCA (gBRCA) mutations were detected in 8 (21%) of the 38 patients who underwent testing, including 6 with gBRCA1 and 2 with gBRCA2), with additional TP53 and SMARC4 detected in one patient each. Approximately 66% of the patients (n = 27) completed surgery post neoadjuvant pembro+CT, of whom 18 (67%) had breast conserving surgery and 9 (33%) had mastectomy. Of the patients who underwent surgery, 60% (n = 16/27) achieved pCR including 68% (13/19) of the IHC 0+ and 37.5% (3/8) of the HER2 1+ or 2+ ISH negative (p-value = 0.429, Chi Square test). Of the total population, 16 (40%) did not complete NACT; 1 lost to follow-up, 9 were still on ongoing therapy, 2 discontinued therapy due to toxicity, and 4 developed progressions including 1 locoregional relapse, and 3 metastatic diseases. Of the 32 patients who completed at least 3 months of pembro-NACT, 14 (34%) reported any grade irAE: skin toxicity (N = 3, 21%), hypothyroidism (N = 8, 57%), Hyperthyroidism (N = 1, 7%), Hepatitis (N = 4, 28.5%), adrenal insufficiency (N = 1, 7%), and pneumonitis (N = 1, 7%). With a median follow up of 4.5 months, pembro was postponed in 4 patients and permanently discontinued in 1 secondary to severe pneumonitis requiring ICU admission. All irARs were graded at I and II, except for 1 grade III dermatitis, and 1 grade III pneumonitis. Interruption of IO was required for irAE in 5 (36%) patients, and steroids were administered in 4 (29%). pCR was observed in 6 (40%) patients out of 15 who experienced treatment interruption due to IrAE or CT and 10 out of 13 (77%) in those who did not experience treatment interruption (p = 0.04895, Chi-square test). Conclusion The pCR rates for Pembro-based NACT in this RWE study, involving patients with an overall higher risk disease, appeared to be consistent with those observed in keynote-522. Interestingly, pCR rates did not seem to differ between HER2 negative and HER2 low groups. However, pCR rates appeared to be lower in patients who experienced treatment interruptions. Approximately half of the patients developed irAE but the majority of the adverse events were of lower grade and did not require treatment interruptions. Overall, the RWE observed in this study supports the ongoing funding and utilization of Pembro-based NACT in eTNBC. Updated data, including the pCR rate and toxicity, will be presented at the meeting once most of the patients have completed surgery. Table 1: Clinical and Pathological Characteristics of patients (Nf41) XX- XX Citation Format: Aydah Al-Awadhi, Mouza AlShebli, Lina Wahba, Tallal Younis. Real-World evidence for Pembrolizumab-based neoadjuvant chemotherapy in early-stage triple negative breast cancer: a single institution experience [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 PO3-17-10.

Antibiothérapie courte au cours de la pneumonie : PNEUMOSHORT

IntroductionPneumonia is one of the most common indications for antibiotic. Shortening the duration of antibiotic therapy should help reduce bacterial resistance. To date, three randomized control trials have shown non-inferiority of short courses of antibiotic therapy (3 days) compared with 7 days in non-severe pneumonia. The aim of this study was to assess this strategy in real life. MethodThis retrospective observational cohort study included all patients with pneumonia hospitalized in an internal medical ward from 11/01/2022 to 05/31/2023. We implemented the strategy based on early discontinuation of antibiotic therapy in patients with pneumonia who were clinically stable after 3 days of β-lactam treatment. ResultsAmong 49 patients included, median age was 72, median antibiotic duration was 4 days (IQR 3-6), and cure rate at D30 was 88 %. At day 30, we observed one death (2 %), four new antibiotic therapy (9 %), and two new hospitalisation (5 %), among five immunosuppressed patients. Among immunosuppressed patients (n=17; 35 %), failure rate was three times higher in case of short antibiotic courses (3/8; 38 %) than long antibiotic courses (1/7; 14 %). ConclusionStrategy based on early discontinuation of antibiotic therapy in immunocompetent patients with pneumonia who were clinically stable after 3 days of β-lactam treatment is safe, and easy to implement in a medical ward.

Follow-up biopsies in gastrointestinal immune checkpoint inhibitor toxicity may show markedly different inflammatory patterns than initial injury

Colitis is a common manifestation of immune checkpoint inhibitor (ICI) toxicity and can present with varied histologic patterns of inflammation, some of which have been shown to be associated with specific ICI drug types. Although the histologic features of ICI colitis seen at the time of diagnosis have been described, there have been few reports following these patients over time. We evaluated initial and follow-up biopsies in 30 patients with ICI colitis and found that 37% of patients developed a different pattern of injury on follow-up biopsy compared to the initial biopsy. Patients with a different inflammatory pattern were more likely to have restarted ICI therapy before their follow-up biopsy (64%) compared to those without a change in inflammatory pattern (11%; P < 0.01). The majority of these patients had changed ICI drug types (86%). Additionally, many cases changed to an inflammatory bowel disease (IBD)-like pattern (36%), raising a question of de novo IBD. However, all of our patients with an IBD-like pattern experienced sustained resolution of symptoms without steroids or other immunosuppressive medications following discontinuation of ICI therapy, consistent with a diagnosis of ICI toxicity. Our findings suggest that follow-up biopsies in patients with ICI colitis may show a different histology and that this does not necessarily warrant a change in the histologic diagnosis to another disease.

Predictors of Nucleos(t)ide Analogues Discontinuation Relapse: Hepatitis B Virus RNA versus Hepatitis B Surface Antigen.

To compare the predictive value of hepatitis B virus (HBV) RNA and HBsAg quantification upon discontinuation of nucleos(t)ide analogues (NAs) therapy for clinical and virological relapse in chronic hepatitis B (CHB). Observational study. Place and Duration of the Study: Department of Infectious Diseases and Hepatology, The Second Hospital of Shandong University, Jinan, China, from July 2014 to December 2020. CHB patients received single NAs and discontinued treatment following appropriate standards. HBsAg quantification was conducted using the i2000 Chemiluminescent Immunoassay (CLIA) Analyser, while serum HBV RNA quantification was performed using specific RNA target capture and simultaneous amplification and testing. The main observational endpoints included virological relapse and clinical relapse. Eighty-one patients were recruited, with 15 patients achieving HBsAg loss at cessation. Twenty-nine individuals encountered virological relapse, while 13 patients experienced clinical relapse. Thirty-one patients achieved HBsAg <100 IU/ml at NAs cessation, among whom 26 achieved undetectable HBV RNA, while four patients suffered virological relapse (15.4%). Serum HBV RNA emerged as an independent determinant of virological relapse (HR 1.850), clinical relapse (HR 2.020), and HBsAg loss after NAs cessation (HR 0.138). The presence of HBsAg <100 IU/ml at cessation did not serve as a predictor for virological relapse and clinical relapse. Lower HBV RNA levels predict a better off-treatment response. Discontinuation of prolonged NAs therapy appears as a viable and safe choice for patients with undetectable HBV RNA. In comparison to HBV RNA, HBsAg <100 IU/ml at cessation did not show sufficient predictive value for virological relapse and clinical relapse. HBV RNA, Hepatitis B surface antigen, Chronic hepatitis B, Relapse.

The impact of growth hormone (GH) therapy on glucose metabolism: A narrative review mainly focused on GH-deficient (GHD) children and adolescents

Introduction: Growth hormone (GH) deficiency (GHD) in children and adolescents is traditionally managed with GH therapy, which, while effective for promoting growth, poses potential metabolic repercussions, particularly concerning glucose metabolism. This review delineates the complex interplay between GH therapy, insulin sensitivity, and glucose homeostasis. Objective: To synthesize existing literature on the effects of GH therapy on glucose metabolism, insulin secretion, and insulin sensitivity in GH-deficient pediatric populations, aiming to illuminate the nuanced metabolic consequences and to optimize therapeutic outcomes. Results: The reviewed studies illuminate a complex influence of GH therapy on metabolic parameters. While GH promotes growth and improves body composition, it may concurrently impair insulin sensitivity, elevate fasting glucose levels, and, in some cases, induce glucose intolerance. However, the dysglycemic effect during GH therapy appears to be transient and reversible on discontinuation of therapy. The counterbalancing role of insulin-like growth factor 1 (IGF-1) and its contribution to maintaining glucose homeostasis is also highlighted, illustrating a complex metabolic interplay induced by GH therapy. Discussion: The findings underscore the variability in individual metabolic responses to GH therapy. The balance between GH-induced insulin resistance and IGF-1-mediated insulin sensitivity is crucial. Monitoring and adjusting GH therapy based on glycemic response is imperative to prevent adverse metabolic outcomes. Conclusion: GH therapy in GH-deficient children and adolescents requires careful consideration of its metabolic effects. Personalized treatment strategies and vigilant monitoring of glucose metabolism are essential to optimize therapeutic outcomes and minimize the risk of metabolic complications. Further research is warranted to establish comprehensive guidelines for managing the metabolic aspects of GH therapy in this vulnerable population.

Long-Term Outcome After Discontinuation of CGRP-Targeting Therapy for Migraine.

Calcitonin gene-related peptide (CGRP)-targeting agents are potential candidates for disease-modifying migraine drugs. However, most studies on CGRP-targeting agents have assessed efficacy outcomes rather than long-term effects after discontinuation. This review aimed to synthesize and scrutinize the latest clinical data on the outcomes after the discontinuation of CGRP-targeting therapy in patients with episodic and chronic migraine, with a particular focus on chronic migraine. Real-world studies involving patients with migraine have reported consistent findings of worsened headache frequency and quality of life after the discontinuation of CGRP monoclonal antibodies (CGRP mAbs). Although many patients maintain improvements for up to 4months after discontinuation compared to baseline (before starting CGRP mAbs), no studies have evaluated the effects of stopping treatment for > 5months, which is the five-half-life of CGRP mAbs. Several studies have suggested that patients treated with CGRP receptor mAbs experience more rapid deterioration than those treated with CGRP ligand mAbs after discontinuing CGRP mAbs. The results of real-world studies suggest that for many patients with migraine, the benefits of CGRP mAbs diminish months after discontinuation. Therefore, anti-CGRP therapies may not be considered disease-modifying. However, the comprehensive assessment of the disease-modifying potential of these drugs requires studies with extended treatment and cessation durations.

Chronic non-bacterial osteomyelitis (CNO) and chronic recurrent multifocal osteomyelitis (CRMO) with a focus on pamidronate therapy.

Chronic recurrent multifocal osteomyelitis (CRMO), also called chronic nonbacterial osteomyelitis (CNO) or nonbacterial osteomyelitis (NBO), is a rare autoinflammatory bone disease of unknown etiology. However, the number of patients properly diagnosed would increase with better knowledge of the disease. In this regard, whole-body magnetic resonance imaging (WB MRI) has been found to be a better predictor of active lesions than clinical examination. Importantly, the RINBO index (radiologic index for NBO) quantifies the involvement based on the WB MRI. Further, a chronic nonbacterial osteomyelitis MRI scoring (CROMRIS) has been developed as an online tool for assessing WB MRI. The therapy consists of non-steroidal anti-inflammatory drugs (NSAIDs), bisphosphonates (pamidronate, zoledronate, etc.) and other drugs, including biologics. Pamidronate is an appropriate and safe therapy. The first pilot prospective randomised controlled trial (RCT) on pamidronate vs. placebo was carried out in adults. No RCT has been done in children yet. Besides RCTs, there are a number of issues to be explored in future, i.e. predictors of therapy effect, optimal therapy duration, predictors of therapy discontinuation and evaluation of optimal therapy protocol. Recently, the CNO clinical disease activity score (CDAS) was constructed and validated but the classification criteria are still being developed. As collaboration on this rare disease is essential, a prospective Chronic Nonbacterial Osteomyelitis International Registry (CHOIR) was established to generate future comparative effectiveness research data.

A review on potential adverse effects associated with Janus-kinase inhibitors

Rheumatoid arthritis (RA) is a chronic, symmetrical, inflammatory autoimmune disease that affects small joints. RA has a population prevalence of 0.5% to 1% in the U.S. The annual cost of care for chronic treatment of RA in the United States is estimated at $12,509. Pharmaceutical companies have developed drugs to treat RA using Janus kinase (JAK) inhibitors. These drugs can have potential adverse effects. Forecasting a better output to JAK inhibitors (JAKI’s). Therapy duration of JAKI’s and Problems regarding to strategies of dose reduction or if the discontinuation of therapy takes place in case of low disease activity. The accurate pharmacological profile and interactions of other drugs with JAKI’s have to establish. Proper safety, efficacy profile of JAKI’s and when administered in combination with DMARD’s. The safety, efficacy data of JAKI’s when compared to non-anti-TNF biologics. Obtaining of experience on JAKI’s that were already existed in the market and further experimental findings on newer compounds and which may clarify many of the aspects which are to be solved in nearer future as these JAKI will have greater application in treatment of RA. Regardless of significant developments in latest years in the pharmacotherapy of RA in the use of JAK inhibitors, yet the adverse effects of JAK inhibitors are unanswered. Therefore, one of the main concerns associated with JAK inhibitor is the potential adverse effects. The challenges can be addressed by clinical pharmacist mediated interventions related to dosing of JAK inhibitors and proper management of adverse drug reactions (ADRs).

Iatrogenic esophageal dysmotility as a barrier to transplantation in pulmonary arterial hypertension

Esophageal dysmotility is identified as a contraindication to lung transplantation at some centers due to increased risks of acute rejection, pulmonary infection, and chronic lung allograft dysfunction. Phosphodiesterase-type 5 inhibitors (PDE5i) are a cornerstone pharmacotherapy for pulmonary arterial hypertension (PAH) and are known to exert off-target effects that may impact lung transplant candidacy, including impaired esophageal contractility and decreased lower esophageal sphincter tone. We report two patients with PAH who were initially declined listing for lung transplantation due to iatrogenic esophageal dysmotility induced by PDE5is. Upon discontinuation of PDE5i therapy, these patients experienced significant improvement in esophageal motility within 14 days and met criteria for transplant listing at their centers. Recognizing and mitigating the off-target effects of PDE5i medications is critical for maximizing access to transplant for patients with PAH.

A Cohort Study to Evaluate Genetic Predictors of Aromatase Inhibitor Musculoskeletal Symptoms: Results from ECOG-ACRIN E1Z11.

Aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS. Postmenopausal women with stage I to III hormone receptor-positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972). Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P=0.017; 50% vs. 39%, P=0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS. We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race.