Hobday, Timothy J.

AbstractLutetium-177-dotatate (177Lu-dotatate), a form of peptide receptor radionuclide therapy, was approved by the U.S. Food and Drug Administration for the treatment of advanced somatostatin receptor–positive gastroenteropancreatic neuroendocrine tumors (NETs) in 2018 based on the promising results of the NETTER-1 trial for grade 1–2 midgut NETs. Here, we present a patient with a grade 3 pancreatic neuroendocrine tumor and BRCA1 germline mutation who had a significant response to 177Lu-dotatate.

Abstract Background Metformin has been associated with lower breast cancer (BC) risk and improved outcomes in observational studies. Multiple biologic mechanisms have been proposed, including a recent report of altered sex hormones. We evaluated the effect of metformin on sex hormones in MA.32, a phase III trial of nondiabetic BC subjects who were randomly assigned to metformin or placebo. Methods We studied the subgroup of postmenopausal hormone receptor-negative BC subjects not receiving endocrine treatment who provided fasting blood at baseline and at 6 months after being randomly assigned. Sex hormone-binding globulin, bioavailable testosterone, and estradiol levels were assayed using electrochemiluminescence immunoassay. Change from baseline to 6 months between study arms was compared using Wilcoxon sum rank tests and regression models. Results 312 women were eligible (141 metformin vs 171 placebo); the majority of subjects in each arm had T1/2, N0, HER2-negative BC and had received (neo)adjuvant chemotherapy. Mean age was 58.1 (SD=6.9) vs 57.5 (SD=7.9) years, mean body mass index (BMI) was 27.3 (SD=5.5) vs 28.9 (SD=6.4) kg/m2 for metformin vs placebo, respectively. Median estradiol decreased between baseline and 6 months on metformin vs placebo (−5.7 vs 0 pmol/L; P < .001) in univariable analysis and after controlling for baseline BMI and BMI change (P < .001). There was no change in sex hormone-binding globulin or bioavailable testosterone. Conclusion Metformin lowered estradiol levels, independent of BMI. This observation suggests a new metformin effect that has potential relevance to estrogen sensitive cancers.

e16691 Background: Recent WHO classification of NET has defined high-grade well-differentiated NET (NET G3) as a distinct entity that is clinically different from neuroendocrine carcinoma. The optimal treatment for NET G3 has not been well-described. This study aims to evaluate NET G3 response to different treatment regimens. Methods: This is a retrospective study of NET G3 patients within the Mayo Clinic database (Arizona, Florida, and Minnesota). Patient demographics along with treatment responses and survival were assessed. Primary end points were progression-free survival (PFS) and objective response rate (ORR) by RECIST 1.1 criteria. Results: 71 patients with NET G3 were identified. Systemic treatment data was available in 30 patients who had a median age of 59.5 years at time of diagnosis. The primary tumor was most commonly pancreatic (73.3%). Ki 67 index was ≥55% in 26.7% of cases. 56.7% of cases had > 1 metastatic site. Treatment regimens included: capecitabine+temozolomide (CAPTEM) (n = 20), somatostatin analog (SSA) (n = 14), carboplatin/cisplatin+etoposide (EP) (n = 7), everolimus (n = 2), FOLFOX (n = 7), and lutetium Lu 177 DOTATATE (PRRT) (n = 10). CAPTEM was the most commonly used regimen (10 first-line, and 10 second-line) with ORR of 35%, disease control rate (DCR) of 65%, and median PFS of 9.4 months. The table summarizes the treatment data and responses rates for the various therapies used. Conclusions: Among NET G3 patients treated at Mayo Clinic, CAPTEM was found to be the most commonly used treatment with reasonable efficacy and disease control. Other treatment options include SSA, PRRT, FOLFOX, and EP. Prospective studies evaluating different treatments effects in NET G3 patients are needed to determine an optimal treatment strategy. [Table: see text]

Objectives A platinum/etoposide doublet is standard first-line therapy for poorly differentiated neuroendocrine carcinoma (PD NEC); however, evidence to guide treatment beyond first-line regimens is lacking. This study aimed to evaluate the efficacy of second-line regimens in PD NEC. Methods We performed a retrospective analysis of patients treated with second-line chemotherapy for PD NEC. Inclusion criteria were previous first-line therapy with platinum/etoposide, extrapulmonary PD NEC, and follow-up data. The primary end points were overall survival (OS) and progression-free survival (PFS) after second-line therapy. Secondary end points included OS and PFS from first-line therapy. Results Sixty-four patients were included. The median OS from initiation of second-line therapy was 6.2 months (95% confidence interval [CI], 4.9–8.9). The median PFS was 2.3 months (95% CI, 2.0–3.2). No second-line regimen showed a statistically significant difference in OS or PFS. There was a significant increase in OS for cisplatin first-line regimens compared with carboplatin (17.0 months [95% CI, 12.5–22.6] vs 11.7 months [95% CI, 8.0–14.0]). Conclusions The efficacy of current second-line therapy in PD NEC is poor. No second-line regimen showed statistically significant superiority. Cisplatin was associated with longer OS regardless of second-line regimen or age. However, unmeasured confounders such as performance status or comorbidities may explain this effect.

Abstract Introduction: CDK 4/6 inhibitors (CDK4/6i) are FDA approved for treatment of hormone receptor (HR) positive, HER2 negative metastatic breast cancer (MBC). Recent work demonstrated that a rise in MCV was correlated with longer median progression free survival (Anampa et al, Haemoatologica 2018). We performed a single-institution retrospective analysis to evaluate whether palbociclib induced early changes in MCV serve as a pharmacodynamic biomarker to predict response to CDK4/6i. Methods: We identified a retrospective cohort of 81 patients with HR+, HER2- MBC treated with CDK4/6i as first line metastatic treatment at Mayo Clinic, Rochester. Hematologic indices were abstracted pretreatment and at the start of each cycle through the start of cycle 4 (C4). Wilcoxon signed test was used to examine the changes in MCV (ΔMCV) comparing pretreatment up to C4 and ΔMCV between cycles. Optimal cut points for ΔMCV were determined using Cutoff finder (Budczies et al., PLOS One 2012). Cox proportional hazard regression analysis was performed to evaluate associations of MCV and time to treatment failure (TTF), which was defined as the time from the start of the analyzed cycle to treatment discontinuation for any reason(in months). As eight comparisons were made, a Bonferroni correction established p-value <0.00625 as the adequate cutoff for statistical significance. Statistical analyses were performed using JMP (SAS Institute Inc, Cary, NC). Results: 60/81 patients had pretreatment and at least one subsequent lab data point that included MCV. The pretreatment mean hemoglobin (Hgb) was 12.8 [standard deviation (SD) 1.37 g/dL] and 6/60 (10.2%) patients with Hgb <11.0 g/dL. Mean pretreatment MCV was 89.0 femtoliters/cell [fl (SD 4.63)] and no macrocytosis (defined as MCV >100 fl) was observed. At C4, the mean Hgb was 12.1 g/dL (SD 1.11) with 4/49 (8.2%) with Hgb <11.0 g/dL. The C4 mean MCV was 96.6 fl (SD 5.23) and 8/29 (16.3%) developed macrocytosis. Wilcoxon signed analysis showed a significant increase in ΔMCV pretreatment to C2 [n=51, median 1.5 with interquartile range (IQR) -0.1-3.2, p<0.0001], C2 to C3 (n=44, median 2.9, IQR 1.4-5.2, p<0.0001), and C3 to C4 (n=41, median 3.4, IQR 1.9-4.9, p<0.0001). A rise in MCV≥8.15 from pretreatment to C4 was associated with a non-statistically significant improvement in TTF [n=49, hazard ratio (HR) 0.38, p = 0.06]. Between C2 and C3, a rise in MCV ≥2.9 was associated favorably with TTF (n=44, HR 0.36, p = 0.029). The estimated probability of remaining on treatment at 30 months was higher in those with C2-C3 ΔMCV ≥2.9 [44.1%; 95% Confidence Interval (CI) 17.3-68.2%] compared to those with a C2-C3 ΔMCV <2.9 (10.1%; 95%CI 1.5-28.7%). Discussion: We observed an increase in MCV in all patients receiving CDK4/6i by start of C4. The rise in MCV during CDK4/6i treatment may reflect drug induced cell-cycle arrest in hematopoietic cells. Evaluation in larger studies is needed to validate dynamic changes in MCV as a predictive biomarker of response to CDK4/6i therapy. Citation Format: Grace Mei Yee Choong, Roberto A Leon-Ferre, Ciara C O'Sullivan, Kathyrn J Ruddy, Tufia C Haddad, Timothy J Hobday, Prema P Peethambaram, Charles L Loprinizi, Minetta C Liu, Vera J Suman, Matthew P Goetz, Karthik V Giridhar. Evaluation of mean corpuscular volume (MCV) as a pharmacodynamic predictive biomarker in patients receiving CDK4/6 inhibitors for metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P1-19-42.

Abstract Background Although physical activity has been consistently associated with reduced breast cancer mortality, evidence is largely based on data collected at one occasion. We examined how pre- and postdiagnosis physical activity was associated with survival outcomes in high-risk breast cancer patients. Methods Included were 1340 patients enrolled in the Diet, Exercise, Lifestyle and Cancer Prognosis (DELCaP) Study, a prospective study of lifestyle and prognosis ancillary to a SWOG clinical trial (S0221). Activity before diagnosis, during treatment, and at 1- and 2-year intervals after enrollment was collected. Patients were categorized according to the Physical Activity Guidelines for Americans as meeting the minimum guidelines (yes/no) and incrementally as inactive, low active, moderately active (meeting the guidelines), or high active. Results In joint-exposure analyses, patients meeting the guidelines before and 1 year after diagnosis experienced statistically significant reductions in hazards of recurrence (hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.42 to 0.82) and mortality (HR = 0.51, 95% CI = 0.34–0.77); associations were stronger at 2-year follow-up for recurrence (HR = 0.45, 95% CI = 0.31 to 0.65) and mortality (HR = 0.32, 95% CI = 0.19 to 0.52). In time-dependent analyses, factoring in activity from all time points, we observed striking associations with mortality for low- (HR = 0.41, 95% CI = 0.24 to 0.68), moderate- (HR = 0.42, 95% CI = 0.23 to 0.76), and high-active patients (HR = 0.31, 95% CI = 0.18 to 0.53). Conclusions Meeting the minimum guidelines for physical activity both before diagnosis and after treatment appears to be associated with statistically significantly reduced hazards of recurrence and mortality among breast cancer patients. When considering activity from all time points, including during treatment, lower volumes of regular activity were associated with similar overall survival advantages as meeting and exceeding the guidelines.

10530 Background: Learner wellbeing may be adversely affected by the experience of discrimination. Eliciting details from this vulnerable population about these experiences is a challenge. This study characterizes trainee experiences of discrimination and inclusion to inform graduate medical education (GME) policies and practice. Methods: Anonymous semi-structured, private phone interviews were conducted with fellows after informed consent. No identifying information was exchanged and the interviewer had no supervisory role over learners. Demographic information was obtained via anonymous online survey. Results: Of 29 fellows approached, 20 consented; 17 interviewed (10 men; median age 32 years). Racial & ethnic distribution: 6 Asian, 2 Black, 2 Multi-racial, 4 White, 3 Hispanic/Latino. All fellows reported discriminatory behavior that they either experienced or witnessed. Incidents of discriminatory behavior towards trainees were more common from patients (pts) (n = 41) than staff (n = 12). Discrimination from pts included requesting a different physician based on accent (n = 13), race (n = 11), perceived avoidance of a trainee considered “different” (n = 11), sex (n = 5), & ethnicity (n = 4). Six trainees were aware of policies against pt discrimination but only 1 trainee reported an incident. Trainees did not report because of the nature of incidents (micro aggressions that are difficult to characterize) and sense of futility of reporting. Discriminatory behavior from staff was based on perceived micro aggressions (n = 4), sex (n = 3), ethnicity (n = 3), ageism (n = 1), and sexual orientation (n = 1). Impact on trainees ranged from negative (personal anguish) to positive (motivation to improve communication). Coping mechanisms included debriefing with family/trainees and focusing on good pt experiences. Trainees felt that having diverse co-fellows, involvement on committees, and supportive program leadership promoted inclusivity. Conclusions: Our study found that discriminatory behavior towards trainees is common. Our methodology allows for honest & safe discussions. GME programs must assess their learning climate with respect to bias/inclusivity & develop appropriate processes.

e20605 Background: Intravenous (IV) fosaprepitant is a potent antiemetic, commonly used in patients receiving chemotherapy. The purpose of this study was to investigate the incidence of IV fosaprepitant-associated infusion site adverse events (ISAEs) among a cohort of breast cancer patients receiving doxorubicin and cyclophosphamide (AC) chemotherapy at Mayo Rochester. Methods: A retrospective review of electronic medical record (EMR) data was performed for all patients who were initiated on AC chemotherapy from January 2011 to April 2012. Data collected from the EMR included baseline demographics, antiemetic regimen, documentation of ISAEs and type of IV access (peripheral vs. central). Descriptive statistics (mean and standard deviation or percentages) were summarized overall and by type of IV access and initially administered antiemetic. Results: 148 patients were included, with a median age of 54 years (range 28-76). 98 patients initially received IV fosaprepitant; 44 oral aprepitant; 6 neither. 132 (89%) initially had peripheral IV access and 16 (11%) had central venous access. Overall, 33 patients (34%) experienced an IV fosaprepitant associated ISAE including: erythema (n=22), pain (n=26), swelling (n=12), infusion site hives (n=5), extravasation (n=4), deep venous thrombosis (n=3), superficial thrombosis (n=7), phlebitis/thrombophlebitis (n=5), venous discoloration (n=1), venous engorgement (n=1), venous hardening/induration (n=4) and local scarring (n=1). Only 1 patient (2%) experienced an oral aprepitant associated ISAE, which was infusion site pain. This patient had previously had a fosaprepitant associated ISAE at the same site. All experienced ISAEs occurred in patients with peripheral IV access. Conclusions: The incidence and severity of ISAEs associated with IV fosaprepitant administration among a group of patients receiving doxorubicin/cyclophosphamide chemotherapy is significant and is appreciably higher than what has been noted in other reports. The higher incidence observed is likely related to the predominance of peripheral venous access used in the studied cohort.

4032 Background: PNET has long had few effective therapies other than chemotherapy. Placebo-controlled phase III trials of the mTOR inhibitor everolimus and the VEGF/PDGF receptor inhibitor sunitinib noted improved progression-free survival (PFS). However, objective response rates (RR) with these agents are still <10%. Preclinical studies suggest enhanced anti-tumor effects with combined mTOR and VEGF targeted therapy. Methods: We conducted a phase II trial of the mTOR inhibitor TEM (25 mg IV q week) and the VEGF-A monoclonal antibody BEV (10 mg/kg IV q 2 weeks) in patients (pts) with well or moderately differentiated PNET and progressive disease by RECIST within 7 months of study entry. Co primary endpoints were RR and 6-month PFS. Planned enrollment was 50 patients, with interim analysis for futility after the first 25 evaluable pts. Pts had no prior mTOR or VEGF targeted agents, ECOG PS 0-1, and adequate hematologic and organ function. Continued octreotide was allowed, but not required. Prior interferon, embolization, and ≤ 2 chemotherapy regimens were allowed. Results: 55 pts were eligible for response assessment. Confirmed PR was documented in 20 of 55 patients (37%). 44 of 55 (80%) patients were progression-free at 6 months. Of 49 pts evaluable for this endpoint, 12 month PFS is 49%. 15 patients remain on therapy. For evaluable patients, the most common grade 3-4 adverse events attributed to therapy were hypertension (18%), hyperglycemia (13%), fatigue (11%). leukopenia (9%), headache (9%), proteinuria (7%), and hypokalemia (7%). Conclusions: The combination of TEM/BEV has substantial activity in a multi-center phase II trial with RR of 37%, well in excess of single targeted agents in PNET. 6-month PFS was a notable 80% in a population of patients with RECIST criteria progression within 7 months of study entry. Phase III trials of combined VEGF/mTOR inhibition in PNET should be pursued. Clinical trial information: NCT01010126.

CRA1008 The full, final text of this abstract will be available at abstract.asco.org at 7:30 AM (EDT) on Monday, June, 3, 2013, and in the Annual Meeting Proceedings online supplement to the June 20, 2013, issue of Journal of Clinical Oncology. Onsite at the Meeting, this abstract will be printed in the Monday edition of ASCO Daily News.