Citations

Background: The study of hypertrophic cardiomyopathy (HCM) can yield insight into the mechanisms underlying the complex trait of cardiac hypertrophy. To date, most genetic variants associated with HCM have been found in sarcomeric genes. Here, we describe a novel HCM-associated variant in the noncanonical Wnt signaling interactor WTIP (Wilms tumor interacting protein) and provide evidence of a role for WTIP in complex disease. Methods: In a family affected by HCM, we used exome sequencing and identity-by-descent analysis to identify a novel variant in WTIP (p.Y233F). We knocked down WTIP in isolated neonatal rat ventricular myocytes with lentivirally delivered short hairpin ribonucleic acids and in Danio rerio via morpholino injection. We performed weighted gene coexpression network analysis for WTIP in human cardiac tissue, as well as association analysis for WTIP variation and left ventricular hypertrophy. Finally, we generated induced pluripotent stem cell–derived cardiomyocytes from patient tissue, characterized size and calcium cycling, and determined the effect of verapamil treatment on calcium dynamics. Results: WTIP knockdown caused hypertrophy in neonatal rat ventricular myocytes and increased cardiac hypertrophy, peak calcium, and resting calcium in D rerio . Network analysis of human cardiac tissue indicated WTIP as a central coordinator of prohypertrophic networks, while common variation at the WTIP locus was associated with human left ventricular hypertrophy. Patient-derived WTIP p.Y233F-induced pluripotent stem cell–derived cardiomyocytes recapitulated cellular hypertrophy and increased resting calcium, which was ameliorated by verapamil. Conclusions: We demonstrate that a novel genetic variant found in a family with HCM disrupts binding to a known Wnt signaling protein, misregulating cardiomyocyte calcium dynamics. Further, in orthogonal model systems, we show that expression of the gene WTIP is important in complex cardiac hypertrophy phenotypes. These findings, derived from the observation of a rare Mendelian disease variant, uncover a novel disease mechanism with implications across diverse forms of cardiac hypertrophy.

5001 Background: In the phase 3 VISION trial, targeted radioligand therapy with lutetium (177Lu) vipivotide tetraxetan ([177Lu]Lu-PSMA-617; 177Lu-PSMA-617) significantly prolonged radiographic progression-free survival (rPFS) and overall survival (OS) when added to standard of care (SoC) in patients with advanced prostate-specific membrane antigen (PSMA) PET-positive metastatic castration-resistant prostate cancer. Benefits were consistent across most pre-specified subgroups. In this post hoc exploratory analysis, we examined rPFS and OS in the context of prior and concomitant cancer-directed treatments. Methods: In VISION, adult patients previously treated with at least 1 androgen receptor pathway inhibitor (ARPI) and 1–2 taxane regimens were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq Q6W, up to 6 cycles) + SoC or SoC alone. Protocol-permitted SoC excluded cytotoxic chemotherapy, systemic radioisotopes, immunotherapy, or other investigational drugs. Exploratory subgroup analyses of rPFS and OS were performed by: number of prior ARPIs; taxane regimens; non-taxane regimens and immunotherapies; prior treatment with bone-sparing agents; 223Ra and PARP inhibitors; and concomitant treatment with ARPIs, radiation therapy, and bone-sparing agents. Results: Prior and concomitant treatments were generally well balanced between study groups (Table). rPFS and OS benefits with 177Lu-PSMA-617 were consistent across all prior treatment subgroups. Notably, there were benefits in patients who had not received a second prior taxane. There were also consistent benefits regardless of concomitant systemic and radiation therapy as part of SoC. Conclusions: The clinical efficacy of 177Lu-PSMA-617 was observed regardless of prior treatment or SoC chosen, suggesting that disease biology rather than prior and concomitant treatment context drives outcomes. Small differences in outcomes between subgroups may warrant further study to understand better the predictors of improved clinical benefit. Clinical trial information: NCT03511664. [Table: see text]

1512 Background: In response to the COVID-19 pandemic, many cancer practices adopted telehealth, including telephone and video appointments. Following a period of initial expansion that began in March 2020, sustained telehealth integration has emerged across the Mayo Clinic Cancer Practice (MCCP) in 2021. The primary objective of this study was to identify factors associated with utilization of telehealth appointments. Methods: A cross-sectional, multi-site, retrospective analysis was conducted across MCCP – a multisite, multiregional cancer practice with tertiary referral campuses in Minnesota, Florida, and Arizona, as well as rural, community-based hospitals and clinics throughout the Upper Midwest. Multivariable models were used to examine the association of patient- and provider-level variables with telehealth utilization. Results: Outpatient appointments conducted in July – August 2019 (n = 32,932) were compared with those from 2020 (n = 33,662) and 2021 (n = 35,486). The rate of telehealth appointment utilization increased from <0.01% in 2019 to 11.0% in 2020 and 14.0% in 2021. The strongest provider-level predictor of telehealth utilization was female physician provider type (OR 1.06, 95% CI 1.01 to 1.11; P = 0.0297), a trend consistently observed across career stages, practice locations and settings in 2020 and 2021. Additionally, while the rate of telehealth utilization was not significantly different at referral and community-based campuses in 2020, providers at referral campuses were significantly more likely to utilize telehealth than community-based campuses in 2021 (OR 1.1, 95% CI 1.01 to 1.12; P = 0.0289). Regarding patient-level factors, rural residence (defined by Rural-Urban Commuting Area codes), which accounted for 44.2% of the patient population, was significantly associated with lower telehealth utilization as compared to patients with urban residences, particularly for video appointments (OR 1.04, 95% CI 1.02 to 1.07; P < 0.0001). Notably, the disparity in telehealth utilization between rural and urban populations was found to be less pronounced in 2021 as compared to 2020. Conclusions: Multivariable analysis across a multi-site, multi-regional cancer practice identified several factors associated with increased telehealth utilization. These included female physician provider type, referral-based campuses, and patients residing in urban settings. A detailed understanding of the factors that influence telehealth utilization – a method of care delivery which represents a “new normal” across many cancer practices – will be essential to enable continued equitable access to high-quality, high-impact, patient-centered cancer care.

555 Background: Women with early-stage breast cancer (BCa) are living longer, and survivorship issues including second primary cancers (SPCs) are therefore increasingly important. This study seeks to determine the risk of SPCs, including contralateral breast cancer (CBCa), in women with early-stage invasive lobular carcinoma (ILC). Methods: The study population consisted of women with BCa diagnosis between 2000-2018 within the NCI Surveillance, Epidemiology, and End Results (SEER v 3.2.9) registry and between 2000-2021 in the Mayo Clinic Cancer Registry. In the SEER registry, the standardized incidence ratios (SIR) for SPCs were estimated for adult women with histologically confirmed early stage (I-III) ILC compared to the development of any primary cancer in the general population. For reference, SIRs for SPCs for a similar patient population with invasive ductal carcinoma (IDC) of the breast were also estimated. For comparison of CBCa between ILC and IDC, follow up records from the Mayo Clinic Cancer Registry were evaluated among adult women who underwent lumpectomy or unilateral mastectomy for early stage ILC or IDC. A multivariable Cox proportional hazards regression was performed to compare the risk of CBCa between ILC and IDC while adjusting for the age at diagnosis, race/ethnicity and estrogen receptor status of the primary tumor. Results: An increased incidence (p<0.05) of any SPCs and second BCa was noted for both ILC and IDC compared to the expected rate of primary cancer in the general population (Table). Interestingly, women with ILC were observed to have a significantly increased incidence of subsequent gastric cancer which was not seen for women with IDC. An SIR >1.5 was noted for subsequent risk of sarcoma, myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) for both ILC and IDC (Table). In the Mayo Clinic Cancer Registry of 2,218 women with ILC and 14,629 women with IDC meeting the inclusion criteria, the 5-year risk of CBCa was 2.6% and 1.5% (log rank statistic p-value =0.001) for ILC and IDC respectively. A significantly increased risk of CBCa was noted in women with ILC (Hazard Ratio 1.82, 95% CI 1.34-2.47, p<0.001) compared to women with IDC in the multivariable analysis. Conclusions: Women with ILC may have an increased risk of SPC and second BCa compared to the risk of any primary cancer in the general population. The increased incidence of gastric cancer and the higher risk of CBCa in ILC survivors compared to women with IDC is intriguing and needs to be investigated further including evaluation of the role of germline genetic factors. [Table: see text]

AbstractIntroductionThe present study aimed to compare the clinical outcomes of heart transplant patients whose donor hearts were preserved with the SherpaPak controlled cold organ system versus the conventional ice storage technique.MethodsAll patients undergoing heart transplantation at our center between January 2019 and April 2021 were divided into two groups according to the technique used during donor heart preservation and transport. The first group consisted of 34 SherpaPak controlled temperature preservation patients, and the second group consisted of 47 patients where the conventional three bags and ice technique was utilized during organ transportation. The two groups were compared based on demographics, operative details, and postoperative outcomes.ResultsThere were no significant differences between the groups regarding Vasoactive Inotropic Score (VIS), Primary Graft Dysfunction (PGD), and the need for a transient pacer. However, the VIS, PGD, and pacing trends were lower in the SherpaPak patients even though the total ischemic and cardiopulmonary bypass times were significantly longer. Furthermore, SherpaPak patients exhibited a shorter stay in the ICU with no severe PGD and mortality.ConclusionThe SherpaPak donor heart preservation provides safe outcomes in heart transplant patients. Further research is needed to utilize this method for longer durations of ischemic time and expand travel distances for organ transportation.

Abstract Purpose Cyclin dependent kinase 4/6 inhibitors (CDK4/6is), in combination with endocrine therapy (ET), are standard either in the first (1L) or second line (2L) setting for the treatment of hormone receptor (HR) positive, HER2-negative metastatic breast cancer (MBC). However, the optimal sequencing of treatments after progression on CDK4/6i remains unknown. We performed a single institution analysis to identify treatments and outcomes after progression on a CDK4/6i. Methods We identified patients with HR-positive, HER2-negative MBC prescribed a CDK4/6i in the 1L or 2L settings from December 2014-February 2018 at Mayo Clinic in Rochester, Minnesota. Outcomes were collected through September 30, 2020. Results Palbociclib, in combination with letrozole or fulvestrant, was the most prescribed CDK4/6i. The 1L and 2L CDK4/6i cohorts exhibited comparable overall survival (OS), but progression free survival (PFS) was longer in the 1L than the 2L cohort [28.2 months (95% CI 19.6–34.9) vs 19.8 months (95% CI 15.7–29.6)]. The most common post-CDK4/6i treatments were PI3K/mTOR inhibitors (PI3K/mTORi), single agent ET, or chemotherapy. PFS in the 1L CDK4/6i cohort following PI3K/mTORi was 8.5 months (95% CI 5.5 months – NE), single-agent ET was 6.0 months (95% CI 3.3–14.0 months), and chemotherapy PFS was 5.4 months (95% CI 3.3 months- NE). Conclusions Following progression on a CDK 4/6i, mPFS was short, with similar PFS times comparing chemotherapy and ET, with slightly longer PFS for targeted strategies (PI3K/mTOR). These results highlight a major need to better understand the mechanisms of CDK4/6i resistance and identify new therapeutic strategies for these patients.

Objectives: The current study aimed to compare the efficacy of the two different prophylactic antibiotic regimens (2-days vs. 7-days) in preventing surgical site infection in coronary artery bypass grafting (CABG). Methods : Patients undergoing CABG were included in this randomized, double-blind, placebo-controlled trial. From 2016 to 2017, 370 cases were allocated to one of two groups. The groups received prophylactic antibiotic therapy for either 2-days or 7-days. All CABG patients were followed for days for surgical site infections. Two of the patients died after surgery, and 3 patients did not show up during the three-month follow-up evaluation and thus did not meet the study criteria. Results: Of the remaining 365 patients who participated in the full study, 198 (54.2%) were male, and 167 (45.7%) were female patients. The mean age of these cases was 58.64± 11.4. Of the 365 study participants who received prophylactic antibiotics prior to surgery, 16 patients developed surgical site infections (legs and sternum). Among these 16 patients, nine cases belong to the 7-days prophylactic antibiotic therapy group (2.4%), and seven cases belong to the 2-day prophylactic antibiotic therapy group (1.9%) (P=0.771). Conclusion: Comparison of two 2-day and 7-day prophylactic antibiotic regimens showed no significant difference in the incidence of post-surgical infection in the two groups.

The NCCN Guidelines for Head and Neck Cancers address tumors arising in the oral cavity (including mucosal lip), pharynx, larynx, and paranasal sinuses. Occult primary cancer, salivary gland cancer, and mucosal melanoma (MM) are also addressed. The specific site of disease, stage, and pathologic findings guide treatment (eg, the appropriate surgical procedure, radiation targets, dose and fractionation of radiation, indications for systemic therapy). The NCCN Head and Neck Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s most recent recommendations regarding management of HPV-positive oropharynx cancer and ongoing research in this area.

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 Background: Cyclin dependent 4/6 kinase inhibitors (CDK4/6i) and endocrine therapy (ET) have improved progression-free survival (PFS) and overall survival in HR+ MBC, but progression of disease ultimately occurs. Apart from HR+ status, there are no clinically available biomarkers that enable oncologists to determine prognosis and predict response to CDK4/6i. An emerging biomarker is serum thymidine kinase 1 (TK1), a secreted marker of proliferation that is prognostic in pts with HR+ HER2- MBC. High levels of TKa are associated with inferior PFS, whereas pts with low TKa levels pretreatment, or TKa levels that decrease on ET and a CDK4/6i, have superior PFS. Notably, TKa levels rebound ≥ 5 days off Pb, with resumption of cell cycling. PROMISE (NCT0281902) is a prospective study that enrolled women with HR+ MBC starting Pb + letrozole (L) in the 1st line [FL] or Pb + fulvestrant in the 2nd line [SL] setting. The trial includes a comprehensive “omic” assessment of blood, tumor, urine and the fecal microbiome to identify novel genomic variants and pathways associated with an early decline in TKa (measured after 2 months or end of cycle [C]2) and PFS. Here, we report the association between i) pre-treatment TKa (pre-TKa) levels and PFS (i.e. from registration to the 1st disease event) and ii) TKa levels at the end of C2 (C2-TKa) and PFS-2 (i.e. from the start of C3 to the 1st disease event).Methods: TKa testing was performed using the DiviTum assay (Biovica). TKa+ disease was defined as ≥ 200 Du/L and TKa- disease as below limit of detection to 200 Du/L. Log-rank test and univariate Cox modeling were used to assess the association between pre-TKa levels and PFS and between end of C2-TKa levels and PFS-2. The database was locked on June 28, 2021. Results: Of 68 pts enrolled, 4 were ineligible and pre-TKa data was unavailable for 4. Of the remaining 60 pts (45 FL, 15 SL), the percentage of pts with pre-TKa+ disease was 33.3% in FL (15/45, 95% CI: 20.0-49.0%), and 46.7% (7/15, 95% CI: 21.4-71.9%) in the SL. The median follow-up time for pts on study was 24 months (range: 2-42 months). There were 22 disease events (13 in FL, 9 in SL). In the FL setting, PFS was significantly shorter for preTKa+ pts compared to preTKa- pts (HR: 4.15, 95% CI:1.35-12.74; p=0.007), but not for SL pts (HR: 1.11, 95% CI: 0.30-4.18, p=0.875). End of C2 TKa data was obtained for pts while on Pb (n=5), or after stopping Pb as follows: 1-4 days (n=9), 5-8 days (n=28) and 9-36 days (n=11). PFS-2 was not associated with C2-TKa in the FL (p=0.834) or SL (p=0.454) settings. An analysis of TKa levels by metastatic site will be presented at the meeting.Conclusions: A secreted biomarker of proliferation (TK1) obtained prior to initiating CDK4/6i and ET for the treatment of HR+ MBC is associated with PFS in pts receiving 1st line Pb + L, but not in those receiving 2nd line Pb + fulvestrant. While the end of C2 TKa levels were not associated with PFS, the interpretability of these data are limited, given treatment delays (0-36 days) prior to starting C3 that may result in TKa rebound. Future studies evaluating the predictive nature of TKa and Pb response should focus on earlier timepoints while on drug. Citation Format: Ciara C O'Sullivan, Jun He, Jason Sinnwell, Vera J Suman, Krishna R Kalari, Peter T Vedell, Ann M Moyer, Xiaojia Tang, Kevin J Thompson, Abe Eyman Casey, Alvaro Moreno-Aspitia, Donald W Northfelt, Minetta C Liu, Tufia C Haddad, Saranya Chumsri, Brendan McMenomy, Prema Peethambaram, Kathryn J Ruddy, Karthik V Giridhar, Roberto A Leon-Ferre, Mattias Bergqvist, Adrian Nordmark, Richard M Weinshilboum, Liewei Wang, Matthew P Goetz. Serum thymidine kinase 1 activity (TKa) levels and progression-free survival (PFS) in patients (pts) with hormone receptor positive (HR+) HER2-negative metastatic breast cancer (MBC) on palbociclib (Pb) and endocrine therapy (ET) [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 P5-13-22.