Citations

Abstract Introduction: Hepatopulmonary syndrome (HPS) is characterized by hypoxemia, portal hypertension, and intrapulmonary shunting and manifests as dyspnea. The portal hypertension may be a result of cirrhosis or non-cirrhotic causes such as nodular regenerative hyperplasia of the liver that is associated with drug therapy. Progressive hypoxemia often occurs despite stable liver function. Ado-trastuzumab emtansine (T-DM1; KADCYLA) is an antibody-drug conjugate comprised of a humanized monoclonal antibody trastuzumab covalently linked to the cytotoxic agent maytansine. T-DM1 is prescribed in the postneoadjuvant setting in persons with residual invasive HER2-positive (HER2+) breast cancer (BC) as well as in persons with metastatic HER2+ BC who were previously treated with trastuzumab and a taxane. Liver toxicities including an asymptomatic, transient increase in transaminases and nodular regenerative hyperplasia that results in portal hypertension have been described; however, HPS secondary to noncirrhotic portal hypertension occurring with long-term exposure to T-DM1 has not been reported. We have identified patients (pts) with this infrequent, yet serious complication, and we aim to better characterize their clinical course to guide earlier detection and hopefully prevent irreversible hypoxic respiratory failure. Methods: Institutional search tools were utilized to identify pts at Mayo Clinic with HER2+ BC treated with T-DM1 in either the postneoadjuvant or metastatic setting. Electronic health records were manually reviewed for HPS criteria including 1) hypoxemia 2) portal hypertension and 3) intrapulmonary shunt/vasodilation confirmed by contrast echocardiogram or macroaggregated albumin lung perfusion scan. For pts meeting criteria for HPS, imaging was independently reviewed by a hepatologist to determine whether there was preexisting liver disease or if changes occurred after initiation of T-DM1. Results: We identified 259 pts with HER2+ BC treated with T-DM1 in the postneoadjuvant (n=70) or metastatic setting (n=185). Four pts met criteria for HPS (1.5%) while receiving T-DM1 for metastatic disease (Table 1; listed in chronological order of onset of HPS). Median age was 43 (range 35 - 53 years), median prior lines of treatment was 1.5 (range 0 - 7), and the median number of cycles of T-DM1 prior to discontinuation was 68.5 (range 51 - 90). All pts had evidence of left atrial enlargement on echocardiogram, and evidence of portal hypertension as determined by the presence of varices, and splenomegaly. Three pts had documented telangiectasias as well as Grade 1-2 elevations in serum transaminases and bilirubin. Elevations in hemoglobin were noted in 2 pts during treatment with T-DM1. All pts had a confirmed intrapulmonary shunt via contrast echocardiogram and a lung perfusion scan. Three pts discontinued T-DM1 after diagnosis of HPS and experienced some clinical improvement in hypoxia. One pt died two months after stopping T-DM1 due to progression of BC. Conclusion: HPS may occur in the setting of prolonged exposure to T-DM1 and can be associated with severe hypoxic respiratory failure. Further data are required to characterize the spectrum of liver injury that occurs with long-term use of T-DM1 to provide further guidance to clinicians as regards monitoring for these adverse effects. Patients who developed hepatopulmonary syndrome while on T-DM1Age, yrsSites of metastases# lines of prior txCycles of T-DM1Presenting sign or symptomsNon-contrast ECHO findingsSupplemental oxygenTransaminitis; hyperbilirubinemiaEvidence of portal hypertensionTelangiectasiasHgb prior to T-DM1Hgb end of txLung perfusion studyContrast ECHOPt 153LN, bone090DOE, hypoxemia, clubbingleft atrial enlargement (62 mg/m2)YesNovarices, splenomegalyNot documented12.9 g/dL10.7 g/dL13.5%Yes, small shuntPt 235LN, bone, liver751DOEleft atrial enlargement (54 mg/m2)YesGrade 1; Grade 2varices, splenomegaly; thrombocytopeniaYes, face and handsn/a11.9 g/dL24%Yes, large shuntPt 338LN, bone251Hyperbilirubinemiaborderline left atrial enlargementYesGrade 1; Grade 2varices, splenomegalyYes, trunk, extremities, face11.7 g/dL16.2 g/dL17.8%Yes, moderate shuntPt 448LN, liver186DOEleft atrial enlargement (49 mg/m2)NoGrade 1; Grade 2varices, splenomegalyYes, trunk12.5 g/dL16.1 g/dL7.9%Yes, large shunt Citation Format: Ally Higgins, Adham K Alkurashi, Patrick S Kamath, Vivek N Iyer, Ciara O'Sullivan, Tufia C Haddad. Hepatopulmonary syndrome with long term use of ado-trastuzumab emtansine (T-DM1) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-03.

Abstract With the application of modern investigative technologies, cholestatic liver diseases of genetic etiology are increasingly identified as the root cause of previously designated “idiopathic” adult and pediatric liver diseases. Here, we review advances in the field enhanced by a deeper understanding of the phenotypes associated with specific gene defects that lead to cholestatic liver diseases. There are evolving areas for clinicians in the current era specifically regarding the role for biopsy and opportunities for a “sequencing first” approach. Risk stratification based on the severity of the genetic defect holds promise to guide the decision to pursue primary liver transplantation versus medical therapy or nontransplant surgery, as well as early screening for HCC. In the present era, the expanding toolbox of recently approved therapies for hepatologists has real potential to help many of our patients with genetic causes of cholestasis. In addition, there are promising agents under study in the pipeline. Relevant to the current era, there are still gaps in knowledge of causation and pathogenesis and lack of fully accepted biomarkers of disease progression and pruritus. We discuss strategies to overcome the challenges of genotype–phenotype correlation and draw attention to the extrahepatic manifestations of these diseases. Finally, with attention to identifying causes and treatments of genetic cholestatic disorders, we anticipate a vibrant future of this dynamic field which builds upon current and future therapies, real‐world evaluations of individual and combined therapeutics, and the potential incorporation of effective gene editing and gene additive technologies.

AbstractBackgroundNodular regenerative hyperplasia (NRH) is a rare condition characterized clinically by the development of non‐cirrhotic portal hypertension. NRH is the histopathological result in the liver of various systemic disease processes including autoimmune disorders, haematological malignancies and medications. However, natural history of this condition has been limited to small case series while patient outcomes pertaining to different aetiologies of NRH are largely unknown.MethodsA retrospective cohort of consecutive patients diagnosed with pathology‐confirmed NRH at Mayo Clinic between 2002 and 2017 was identified. The histological diagnosis of NRH was determined by expert liver pathologists. Patients with metastatic liver disease, history of liver transplantation or younger than 18 were excluded. Potential aetiologies of NRH were classified as haematological, rheumatological, drug‐associated, miscellaneous or idiopathic. Long‐term mortality was analysed using Kaplan‐Meier estimation and Cox regression models.ResultsOne hundred and sixty‐seven consecutive patients with pathology‐confirmed NRH were analysed over a 15‐year period and followed for a median time of 50 months (1–306 months). The mean age at diagnosis was 53 years. No aetiology or risk factor for NRH was identified in the majority of patients (94, 56.3%), whereas an associated, possibly causal, condition was found in 73 patients (secondary NRH). The most common presenting feature was elevated liver tests (80%), but no significant differences in laboratory tests were seen based on aetiology of NRH. Compared to idiopathic NRH, those with an identified cause had a higher rate of splenomegaly at presentation (54% vs. 27%, p = 0.002). Portal hypertension‐related complications at diagnosis were common, with ascites present in one‐third of patients. Overall transplant‐free survival was 63% at 5 years. Median survival in idiopathic NRH was 9.4 years compared to 7.3 years in secondary NRH. Age, renal function and volume status at presentation were significantly associated with survival; however, MELD score was not.ConclusionsThe rates of liver‐related complications and mortality in NRH are low, and only a small number of patients ultimately require liver transplantation. Most patients do not have an identified risk factor or aetiology for NRH, and liver‐related outcomes do not appear to differ based on associated, possibly causal, conditions.

TPS376 Background: Human epidermal growth factor receptor 2 ( HER2) gene amplification or protein overexpression (HER2+) occurs in many gastrointestinal (GI) cancers; thus, there is interest in evaluating HER2-targeted therapies in these tumor types. Tucatinib (TUC) is a highly selective HER2-directed tyrosine kinase inhibitor with minimal EGFR inhibition, approved in multiple regions for HER2+ metastatic breast cancer. In patient-derived xenograft models of HER2+ tumors (including esophageal, gastric, and colorectal cancers), TUC + trastuzumab showed superior anti-tumor activity compared with either agent alone (Kulukian 2020). In the MOUNTAINEER study, TUC + trastuzumab in HER2+ metastatic colorectal cancer (CRC) resulted in an objective response rate of 52% and a median duration of response of 10.4 months (interim results, Strickler 2019). The SGNTUC-024 study (NCT04430738) will evaluate TUC + trastuzumab with and without oxaliplatin-based chemotherapy or pembrolizumab in patients with unresectable or metastatic GI cancers. Methods: SGNTUC-024 is an open-label, dose escalation and expansion phase 1b/2 trial. Phase 1b assesses the safety and tolerability of TUC + trastuzumab + either FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine and oxaliplatin) with or without pembrolizumab. One chemotherapy-free cohort is planned (TUC + trastuzumab + pembrolizumab). The initial phase 1b cohort enrolled patients with gastric, esophageal, and gastroesophageal junction (GEJ) adenocarcinomas; cholangiocarcinoma; gallbladder carcinoma; and CRC to receive TUC (150 mg oral [PO] twice daily [BID]) + trastuzumab + FOLFOX. Subsequent phase 1b cohorts will receive TUC (300 mg PO BID) + trastuzumab + either FOLFOX or CAPOX. Once the recommended dose for use with oxaliplatin is identified, cohorts enrolling patients with gastric, esophageal, and GEJ adenocarcinomas will open with patients receiving TUC (300 mg PO BID) + trastuzumab + pembrolizumab with or without either FOLFOX or CAPOX. Phase 2 will expand the assessment of safety and efficacy and enroll 2 cohorts: patients with gastric, esophageal, and GEJ adenocarcinomas (to receive TUC + trastuzumab + pembrolizumab + either FOLFOX or CAPOX, Cohort A) and patients with CRC (to receive TUC + trastuzumab + FOLFOX, Cohort B). Safety and efficacy will be summarized with descriptive statistics. Patients that receive chemotherapy must be eligible for an oxaliplatin-based regimen as standard of care. Patients with irradiated or resected central nervous system (CNS) lesions may enroll, and patients with known active CNS lesions may be eligible for phase 2. The phase 1b portion of the trial is currently enrolling. Clinical trial information: NCT04430738.