Citations

Abstract Background: Cyclin dependent 4/6 kinase inhibitors (CDK4/6i) and endocrine therapy (ET) have improved progression-free survival (PFS) and overall survival in hormone-receptor (HR)-positive metastatic breast cancer (MBC), but progression of disease is inevitable. Serum thymidine kinase-1 (TK1) is a secreted marker of proliferation that is prognostic in patients (pts) with HR-positive, HER2-negative MBC and may be predictive of ET and CDK 4/6i response. PROMISE (NCT0281902) is a prospective study enrolling women with HR-positive MBC starting palbociclib (Pb) + letrozole (L) (1st line) or Pb + fulvestrant (2nd line). We undertook a comprehensive “omic” assessment of blood, tumor, urine and the fecal microbiome in order to identify novel genomic variants and pathways associated with an early decline in TK1 (measured after 2 months) and PFS. Additionally, patient derived xenografts/organoids were generated at baseline and progression to test new therapeutic approaches to overcome resistance to CDK4/6i and ET. We report the initial association between the baseline genomic landscape and baseline TK1 levels. Methods: FFPE tumor biopsies were obtained for DNA/RNA sequencing (TempusTM) and blood samples for TK1 (Divitum® assay, Biovica) were collected pretreatment (pre-Pb) and after 2 cycles of Pb + ET (post-Pb2). Both whole-exome (exome capture) sequencing (WES) and RNA-Seq used the Integrated DNA Technologies xGen Exome Research Panel v1.0 capture kit. TK1+ disease was defined as > 200 Du/L and TK1- disease as below limit of detection up to 200 Du/L. We tested the association between genomic and transcriptomic characteristics with baseline TK1 data in pretreatment samples where both WES and RNA-seq and TK1 was available. The data were analyzed using bioinformatics pipelines for somatic and germline mutations and copy number alterations. The current analysis focuses on baseline 1st-line pre-Pb omics data in conjunction with baseline TK1 levels. The database was locked for analysis on 5/29/2020. Results: Thirty-three pts (median age: 59 yrs.) were evaluable, with paired samples for TK1 in 32. Six pts had TK1+ disease pre-Pb and post-Pb2. Twenty-two pts had TK1- disease pre-Pb and post-Pb2. Four pts had a decrease in TK1 after 2 cycles of treatment that altered the classification from TK1+ to TK1-. Both baseline RNA seq and serum TK1 (n=16) were available for 4 TK1+ and 12 TK1- pts. In this group, 476 genes were differentially regulated (398 upregulated; 78 downregulated). Pathway analysis demonstrated enrichment in complement and coagulation cascade pathway, PPAR signaling pathway, and metabolism-related pathways related to up-regulation of CYP and UGT gene families. Further testing for the association of WES data with baseline TK1+ (n=8) and TK1- (n=16) disease demonstrated somatic copy number variations on chromosomes 6, 11, 12 and 15. CDK4 copy number gains were observed in 3/8 TK1+ pts and 0/16 TK1- pts. We also observed that somatic mutations (LOH, copy number and/or SNV/INDELs) were more prevalent in the TK1+ compared to the TK1- pre-Pb group in several cancer-associated genes (FAS [p=0.06] PTEN, PIK3CB, NAB2, SOX9 and FAT1 [p=0.08], TP53, and MAP2K4 [p=0.22]). Conversely, we also noted that 6/7 pts with GATA3 mutations had TK1- disease (p=0.23). Conclusions: Using a comprehensive “omics” approach, our data suggest that a secreted biomarker of proliferation (TK1) obtained prior to initiating CDK4/6i and ET for the first line treatment of HR+ MBC is associated with established and novel genes and pathways associated with prognosis of pts receiving ET and CDK 4/6i. Analysis of on-treatment (after 2 cycles) tumor RNA seq and its association with change in TK1 as well as data from the 2nd-line cohort will be presented at the meeting. Citation Format: Ciara C O Sullivan, Krishna R Kalari, Vera J Suman, Peter T Vedell, Ann Moyer, Abraham D Eyman Casey, Jason Sinnwell, Xiaojia Tang, Kevin Thompson, Alvaro Moreno-Aspitia, Donald W Northfelt, Minetta C Liu, Tufia C Haddad, Saranya Chumsri, Prema Peethambaram, Kathryn J Ruddy, Karthik V Giridhar, Roberto A Leon-Ferre, Adrian Nordmark, Mattias Bergqvist, Brendan P McMenomy, Richard M Weinshilboum, Liewei Wang, Matthew P Goetz. Novel genomic variants and pathways associated with baseline serum thymidine kinase 1 levels in HR-positive HER2-negative MBC patients commencing palbociclib and letrozole [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-24.

Abstract Background: In ER+ breast cancer (BC) models, Aurora A kinase (AURKA) activation is associated with expansion of CD44+/CD24low/- tumor initiating cells, down-regulation of ERα, and endocrine therapy resistance. Alisertib, a selective AURKA inhibitor, can restore ERα expression and endocrine sensitivity. Early phase studies evaluating alisertib alone or with fulvestrant for ER+ metastatic BC (MBC) demonstrated a favorable safety profile and promising antitumor activity [Haddad, Breast Cancer Res Treat. 2018]. A phase II trial was conducted to determine if the addition of fulvestrant to alisertib improved objective response rate (ORR) and to assess clinical activity of alisertib alone or with fulvestrant in patients (pts) with prior fulvestrant and CDK 4/6 inhibitor (CDK 4/6i). Methods: Pts were randomized 1:1 to Arm A, alisertib (50 mg PO BID Days 1-3, 8-10, 15-17 q 28 days) or Arm B, alisertib with fulvestrant (500 mg IM Day 1, 15 for Cycle 1 and q 28 days thereafter). Eligibility included postmenopausal women, history of ER+ BC, prior fulvestrant, ≤ 2 prior chemotherapy lines, and measurable disease. Stratification factors included prior CDK4/6i, ER level (<10%, ≥10%), and primary/secondary endocrine resistance. Pts on Arm A could cross over to Arm B at progression. With 45 pts per arm, a one sided alpha=0.15 sequential binomial test would have an 85% chance of detecting an increase of ≥ 20% in the ORR of ArmB when the true ORR for Arm A is ≤ 20%. ORR was defined as a partial response (PR) + complete response (CR) by RECIST v.1.1 criteria. Secondary endpoints include progression free survival (PFS), 24-week clinical benefit rate (CBR = CR + PR + absence of progression for> 6 cycles), overall survival, duration of response (DoR), and safety. Blood and tumor specimens were collected at baseline, end of Cycle 1, and progression. Results: Pts enrolled July 2017 - November 2019 with 118 pre-registered, 96 registered, and 90 evaluable for the primary endpoint (Arm A: 45, Arm B: 45). Median age was 60 (range 33, 85). Nearly all received prior fulvestrant (n=89, 98.9%), aromatase inhibitor (n=83, 92.2%), and CDK4/6i (n=88, 97.8%). Most had secondary endocrine resistance (n=71, 78.9%). Pre-registration biopsy for ER was positive in 84 pts (86.7%) and negative in 6 pts (13.3%). More pts on Arm B had prior everolimus (A: 35.6%, B: 57.8%) and prior chemotherapy (A: 44.4%, B: 55.6%) for MBC. The ORR for alisertib and fulvestrant was 20.0% (90% CI: 10.9-32.3%), not significantly greater than alisertib alone 17.8% (90% CI: 9.2-29.8%). The 24-week CBR for Arm A was 42.2% (90% CI: 29.7-55.6%; n=19, including 7 PR) and Arm B was 31.1% (90% CI: 19.9-44.3%; n=14, including 8 PR). As of July 1, 2020, the median DoR was not reached in either arm. The median PFS time was 5.6 months (95% CI: 3.9 - 9.3) for Arm A and 5.1 months (95%CI: 3.8 - 7.6) for Arm B. Seventeen pts (18.9%) remain on treatment (A: 12, B: 5) having received at least 11 cycles (range up to 32+ cycles). At least one dose reduction was required for pts (A: 19, B: 18), most commonly due to neutropenia. The most common severe (grade ≥3) adverse events included neutropenia (n=19, 42.2% in each arm), anemia (A: 15.6%, B: 8.8%), and fatigue (n=5, 11.1% Arm B only). Pts discontinued therapy due to disease progression equally in each arm (n=28, 62.2%), however more pts on Arm B (n=12) than Arm A (n=5) discontinued therapy due to toxicity, refusal or other reasons. Conclusion: While the addition of fulvestrant to alisertib did not improve ORR, promising clinical activity with alisertib monotherapy was observed overall and notably for pts with endocrine and CDK 4/6i-resistant MBC. More severe toxicities and treatment discontinuation were observed in pts receiving combination therapy. Correlative blood (CTC/cfDNA) and tissue (AURKA, ERα, and stemness biomarkers) studies are underway. Citation Format: Tufia Haddad, Antonino D'Assoro, Vera Suman, Jodi Carter, Brendan McMenomy, Erica Mayer, Meghan Karuturi, Aki Morikawa, Paul Marcom, Claudine Isaacs, Sun Young Oh, Amy Clark, Ingrid Mayer, Khandan Keyomarsi, Roberto Leon-Ferre, Karthik Giridhar, Ciara O'Sullivan, Prema Peethambaram, Timothy Hobday, Minetta Liu, James Ingle, Matthew Goetz. Randomized phaseII trial to evaluate alisertib alone or combined with fulvestrant for advanced, endocrine-resistant breast cancer (TBCRC 041) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-05.

Inflammatory breast cancer is a highly aggressive form of breast cancer that forms clusters of tumor emboli in dermal lymphatics and readily metastasizes. These cancers express high levels of E-cadherin, the major mediator of adherens junctions, which enhances formation of tumor emboli. Previous studies suggest that E-cadherin promotes cancer when the balance between apical and basolateral cadherin complexes is disrupted. Here, we used immunohistochemistry of inflammatory breast cancer patient samples and analysis of cell lines to determine the expression of PLEKHA7, an apical adherens junction protein. We used viral transduction to re-express PLEKHA7 in inflammatory breast cancer cells and examined their aggressiveness in 2D and 3D cultures and in vivo. We determined that PLEKHA7 was deregulated in inflammatory breast cancer, demonstrating improper localization or lost expression in most patient samples and very low expression in cell lines. Re-expressing PLEKHA7 suppressed proliferation, anchorage independent growth, spheroid viability, and tumor growth in vivo. The data indicate that PLEKHA7 is frequently deregulated and acts to suppress inflammatory breast cancer. The data also promote the need for future inquiry into the imbalance between apical and basolateral cadherin complexes as driving forces in inflammatory breast cancer.

Abstract Background Pancreatic cystic lesions (PCLs) are increasingly found on cross-sectional imaging, with the majority having a low risk for malignancy. The added value of fine-needle aspiration (FNA) in risk stratification remains unclear. We evaluated the impact of three FNA needles on diagnostic accuracy, clinical management, and the ability to accrue fluid for tumor markers. Methods A multicenter prospective trial randomized 250 patients with PCLs ≥ 13 mm 2:1:1 to 19G Flex, 19G, and 22G needles with crossover for repeated FNA procedures. Diagnostic accuracy was established at 2-year follow-up, with the final diagnosis from surgical histopathology or consensus diagnosis by experts based sequentially on clinical presentation, imaging, and aspirate analysis in blinded review. Results Enrolled patients (36 % symptomatic) had PCLs in the head (44 %), body (28 %), and tail (26 %). Percentage of cyst volume aspirated was 78 % (72 % – 84 %) for 19G Flex, 74 % (64 % – 84 %) for 22G, and 73 % (63 % – 83 %) for 19G (P = 0.84). Successful FNA was significantly higher for 19G Flex (89 % [82 % – 94 %]) and 22G (82 % [70 % – 90 %]) compared with 19G (75 % [63 % – 85 %]) (P = 0.02). Repeated FNA was required more frequently in head/uncinate lesions than in body and tail (P < 0.01). Diagnostic accuracy of the cyst aspirate was 84 % (73 % – 91 %) against histopathology at 2-year follow-up (n = 79), and 77 % (70 % – 83 %) against consensus diagnosis among nonsurgical cases (n = 171). Related serious adverse events occurred in 1.2 % (0.2 % – 3.5 %) of patients. Conclusions Our study results demonstrate a statistically significant difference among the three needles in the overall success rate for aspiration, but not in the percentage of cyst volume aspirated. Flexible needles may be particularly valuable in sampling cystic PCLs in the pancreatic head/uncinate process.

Abstract Concomitant lung transplantation and coronary artery bypass grafting operation became more prevalent over the last decade due to the advanced age of recipients. Median sternotomy approach is traditionally used when internal thoracic artery is utilized. Here we report a technique of harvesting the left internal thoracic artery via a clamshell incision for a combined coronary artery bypass and bilateral lung transplant operation in a 71-year-old male with terminal respiratory failure and coronary artery disease.

48 Background: Improving new patient access to medical oncology clinics is a priority. Unlike external referrals which undergo a review process, internal referrals (from any Mayo department or community-based, affiliated health system) are scheduled directly. At times, these internal referrals lack necessary clinical information, or may be more appropriate for electronic consultation (e-consult). This impacts the patient experience, provider satisfaction, and access to new patient visits. A pilot program was implemented in the Medical Oncology breast clinic to review new internal referrals prior to scheduling. Methods: In 2018, all internally referred patients to Medical Oncology breast clinic were reviewed by an advanced practice provider in breast oncology. Electronic medical records were reviewed to collect diagnosis, pathology, radiology information and treatment to date. Internal referrals were either accepted directly to medical oncology breast clinic, triaged to an internal medicine clinic for workup of a new breast mass, converted to an e-consult, or declined as no medical oncology need was identified. Results: 52 patients were referred internally to Medical Oncology breast clinic. Of these, 29 (55.8%) were accepted directly as new consultations, 8 (15.4%) were triaged to the Internal Medicine clinic, 6 (11.5%) were converted to e-consults, and 6 (11.5%) were declined as not requiring breast medical oncology input. Of the 8 patients that started in the IM clinic, 6 eventually required Medical Oncology breast clinic consults for invasive breast cancers. The most common e-consult was for extending adjuvant endocrine therapy (3/6). 1/6 e-consults required a follow up consultation. The most common reason for declining a consult was no diagnosis of an invasive breast cancer (4/6). A total of 16/52 referrals (30.2%) did not require a breast oncology new consultation. Conclusions: Review of internal referrals improved the efficiency of new breast cancer medical oncology consultations. This review process has been implemented across the entire Medical Oncology practice.

Abstract Background and study aims The Full-Thickness Resection Device (FTRD) provides a novel treatment option for lesions not amenable to conventional endoscopic resection techniques. There are limited data on the efficacy and safety of FTRD for resection of upper gastrointestinal tract (GIT) lesions. Patients and methods This was an international multicenter retrospective study, including patients who had an endoscopic resection of an upper GIT lesion using the FTRD between January 2017 and February 2019. Results Fifty-six patients from 13 centers were included. The most common lesions were mesenchymal neoplasms (n = 23, 41 %), adenomas (n = 7, 13 %), and hamartomas (n = 6, 11 %). Eighty-four percent of lesions were located in the stomach, and 14 % in the duodenum. The average size of lesions was 14 mm (range 3 to 33 mm). Deployment of the FTRD was technically successful in 93 % of patients (n = 52) leading to complete and partial resection in 43 (77 %) and 9 (16 %) patients, respectively. Overall, the FTRD led to negative histological margins (R0 resection) in 38 (68 %) of patients. A total of 12 (21 %) mild or moderate adverse events (AEs) were reported. Follow-up endoscopy was performed in 31 patients (55 %), on average 88 days after the procedure (IQR 68–138 days). Of these, 30 patients (97 %) did not have any residual or recurrent lesion on endoscopic examination and biopsy, with residual adenoma in one patient (3 %). Conclusions Our results suggest a high technical success rate and an acceptable histologically complete resection rate, with a low risk of AEs and early recurrence for FTRD resection of upper GIT lesions.

Abstract Background: I-SPY2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint risk to evaluate novel agents as neoadjuvant therapy for breast cancer. The primary endpoint is pathologic complete response (pCR, ypT0/is ypN0)). DNA repair deficiency in cancer cells can lead to immunogenic neoantigens, activation of the STING pathway, and PARP inhibition can also upregulate PD-L1 expression. Based on these rationales we tested the combination of durvalumab (anti-PDL1), olaparib (PARP inhibitor) and paclitaxel in I-SPY2. Methods: Women with tumors ≥ 2.5 cm were eligible for screening. Only HER2 negative (HER2-) patients were eligible for this treatment, hormone receptor positive (HR+) patients had to have MammaPrint high molecular profile. Treatment included durvalumab 1500 mg every 4 weeks x 3, olaparib 100 mg twice daily through weeks 1-11 concurrent with paclitaxel 80 mg/m2 weekly x 12 (DOP) followed by doxorubicin/cyclophosphamide (AC) x 4. The control arm was weekly paclitaxel x 12 followed by AC x 4. All patients undergo serial MRI imaging and imaging response at 3 & 12 weeks combined with accumulating pCR data are used to estimate, and continuously update, predicted pCR rate for the trial arm. Regimens “graduation with success” when the Bayesian predictive probability of success in a 300-patient phase 3 neoadjuvant trial in the appropriate biomarker groups reaches &gt; 85%. Results: A total of 73 patients received DOP treatment including 21 HR- tumors (i.e. triple-negative breast cancer, TNBC) and 52 HR+ tumors between May 2018 - June 2019. The control group included 299 patients with HER2- tumors. The DOP arm graduated in June 2019, 13 months after enrollment had started, for all HER2- negative and the HR+/HER2- cohorts with &gt; 0.85% predictive probabilities of success. 72 patient completed surgery and evaluable for pCR, the final predicted probabilities of success in a future phase III trial to demonstrate higher pCR rate with DOP compared to control are 81% for all HER2- cancers (estimated pCR rate 37%), 80% for TNBC (estimated pCR rate 47%) and 74.5% for HR+/HER2- patients (estimated pCR rate 28%). Association between pCR and germline BRCA status and immune gene expression including PDL1 will be presented at the meeting. No unexpected toxicities were seen, but 10 patients (14%) had possibly immune or olaparib related grade 2/3 AEs (3 pneumonitis, 2 adrenal insufficiency, 1 colitis, 1 pancreatitis, 2 elevated LFT, 1 skin toxicity, 2 hypothyroidism, 1 hyperthyroidism, 1 esophagitis). Conclusion: I-SPY2 demonstrated a significant improvement in pCR with durvalumab and olaparib included with paclitaxel compared to chemotherapy alone in women with stage II/III high-risk, HER2-negative breast cancer, improvement was seen in both the HR+ and TNBC subsets. Citation Format: Lajos Pusztai, Hyo S. Han, Christina Yau, Denise Wolf, Anne M. Wallace, Rebecca Shatsky, Teresa Helsten, Judy C. Boughey, Tufia Haddad, Erica Stringer-Reasor, Carla Falkson, A. Jo Chien, Rita Mukhtar, Anthony Elias, Borges Virginia, Rita Nanda, Douglas Yee, Kevin Kalinsky, Kathy S. Albain, Aixa Soyano Muller, Kathleen Kemmer, Amy S. Clark, Claudine Isaacs, Alexandra Thomas, Nola Hylton, W. Fraser Symmans, Jane Perlmutter, Michelle Melisko, Hope S. Rugo, Richard Schwab, Amy Wilson, Amy Wilson, Ruby Singhrao, Smita Asare, Laura J. van't Veer, Angela M. DeMichele, Ashish Sanil, Donald A. Berry, Laura J. Esserman, Trial Consortium I-SPY 2. Evaluation of durvalumab in combination with olaparib and paclitaxel in high-risk HER2 negative stage II/III breast cancer: Results from the I-SPY 2 TRIAL [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT011.