Matthew Maurer

Phase I/II study of pilaralisib (SAR245408) in combination with trastuzumab or trastuzumab plus paclitaxel in trastuzumab-refractory HER2-positive metastatic breast cancer

AbstractnThis phase I/II dose-escalation study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and efficacy of the pan-class I phosphoinositide 3-kinase inhibitor pilaralisib in combination with trastuzumab (Arm 1) or trastuzumab plus paclitaxel (Arm 2) in patients with HER2-positive metastatic breast cancer. Patients had progressed on prior trastuzumab (Arms 1 and 2) and received prior taxane (Arm 2). The MTD of pilaralisib was determined using a 3xa0+xa03 dose-escalation design (starting dose 200xa0mg once daily). Forty-two patients were enrolled (21 in each arm). Five patients had a dose-limiting toxicity (DLT; three in Arm 1 and two in Arm 2). Dose-limiting toxicities were rash (three patients) and neutropenia (two patients). The MTD of pilaralisib was determined at 400xa0mg once daily in both arms. The most frequently reported treatment-related adverse events (AEs) were diarrhea (23.8xa0% in Arm 1 vs. 66.7xa0% in Arm 2), fatigue (14.3 vs. 42.9xa0%), and rash (33.3 vs. 38.1xa0%). The most frequently reported treatment-related grade ≥3 AEs were erythematous rash (9.5xa0%) in Arm 1 and diarrhea, peripheral neuropathy, and neutropenia (14.3xa0% each) in Arm 2. Steady-state pilaralisib exposure was similar to previous studies with pilaralisib monotherapy. No responses occurred in Arm 1; four of 20 evaluable patients (20xa0%) in Arm 2 had a partial response. Observed PIK3CA mutations in cell-free circulating DNA did not correlate with response. Pilaralisib in combination with trastuzumab with or without paclitaxel had an acceptable safety profile in metastatic HER2-positive breast cancer, with clinical activity in the paclitaxel arm.

A Synthetic Dosage Lethal Genetic Interaction Between CKS1B and PLK1 Is Conserved in Yeast and Human Cancer Cells

The CKS1B gene located on chromosome 1q21 is frequently amplified in breast, lung, and liver cancers. CKS1B codes for a conserved regulatory subunit of cyclin–CDK complexes that function at multiple stages of cell cycle progression. We used a high throughput screening protocol to mimic cancer-related overexpression in a library of Saccharomyces cerevisiae mutants to identify genes whose functions become essential only when CKS1 is overexpressed, a synthetic dosage lethal (SDL) interaction. Mutations in multiple genes affecting mitotic entry and mitotic exit are highly enriched in the set of SDL interactions. The interactions between Cks1 and the mitotic entry checkpoint genes require the inhibitory activity of Swe1 on the yeast cyclin-dependent kinase (CDK), Cdc28. In addition, the SDL interactions of overexpressed CKS1 with mutations in the mitotic exit network are suppressed by modulating expression of the CDK inhibitor Sic1. Mutation of the polo-like kinase Cdc5, which functions in both the mitotic entry and mitotic exit pathways, is lethal in combination with overexpressed CKS1. Therefore we investigated the effect of targeting the human Cdc5 ortholog, PLK1, in breast cancers with various expression levels of human CKS1B. Growth inhibition by PLK1 knockdown correlates with increased CKS1B expression in published tumor cell data sets, and this correlation was confirmed using shRNAs against PLK1 in tumor cell lines. In addition, we overexpressed CKS1B in multiple cell lines and found increased sensitivity to PLK1 knockdown and PLK1 drug inhibition. Finally, combined inhibition of WEE1 and PLK1 results in less apoptosis than predicted based on an additive model of the individual inhibitors, showing an epistatic interaction and confirming a prediction of the yeast data. Thus, identification of a yeast SDL interaction uncovers conserved genetic interactions that can affect human cancer cell viability.

Improved Cardiovascular Disease Outcomes in Older Adults

Longevity is increasing and the population of older adults is growing. The biology of aging is conducive to cardiovascular disease (CVD), such that prevalence of coronary artery disease, heart failure, valvular heart disease, arrhythmia and other disorders are increasing as more adults survive into old age. Furthermore, CVD in older adults is distinctive, with management issues predictably complicated by multimorbidity, polypharmacy, frailty and other complexities of care that increase management risks (e.g., bleeding, falls, and rehospitalization) and uncertainty of outcomes. In this review, state-of-the-art advances in heart failure, acute coronary syndromes, transcatheter aortic valve replacement, atrial fibrillation, amyloidosis, and CVD prevention are discussed. Conceptual benefits of treatments are considered in relation to the challenges and ambiguities inherent in their application to older patients.

Long-term diet and biomarker changes after a short-term intervention among Hispanic breast cancer survivors: The ¡Cocinar Para Su Salud! randomized controlled trial

Background: Among Hispanic breast cancer survivors, we examined the long-term effects of a short-term culturally based dietary intervention on increasing fruits/vegetables (F/V), decreasing fat, and changing biomarkers associated with breast cancer recurrence risk. Methods: Spanish-speaking women (n = 70) with a history of stage 0–III breast cancer who completed treatment were randomized to ¡Cocinar Para Su Salud! (n = 34), a culturally based 9-session program (24 hours over 12 weeks, including nutrition education, cooking classes, and food-shopping field trips), or a control group (n = 36, written dietary recommendations for breast cancer survivors). Diet recalls, fasting blood, and anthropometric measures were collected at baseline, 6, and 12 months. We report changes between groups at 12 months in dietary intake and biomarkers using 2-sample Wilcoxon t tests and generalized estimating equation (GEE) models. Results: At 12 months, the intervention group compared with the control group reported higher increases in mean daily F/V servings (total: +2.0 vs. −0.4; P < 0.01), and nonsignificant decreases in the percentage of calories from fat (−2.2% vs. −1.1%; P = 0.69) and weight (−2.6 kg vs. −1.5 kg; P = 0.56). Compared with controls, participants in the intervention group had higher increases in plasma lutein (+20.4% vs. −11.5%; P < 0.01), and borderline significant increases in global DNA methylation (+0.8% vs. −0.5%; P = 0.06). Conclusions: The short-term ¡Cocinar Para Su Salud! program was effective at increasing long-term F/V intake in Hispanic breast cancer survivors and changed biomarkers associated with breast cancer recurrence risk. Impact: It is possible for short-term behavioral interventions to have long-term effects on behaviors and biomarkers in minority cancer patient populations. Results can inform future study designs. Cancer Epidemiol Biomarkers Prev; 25(11); 1491–502. ©2016 AACR.

Extent and severity of coronary artery disease by coronary CT angiography is associated with elevated left ventricular diastolic pressures and worsening diastolic function

BACKGROUNDnPatients with flow-limiting coronary stenoses exhibit elevated left ventricular end-diastolic pressure (LVEDP) and abnormal left ventricular (LV) relaxation.nnnOBJECTIVEnWe investigated the relationship of extent and severity of coronary artery disease (CAD) by coronary CT angiography (CTA) to LVEDP and measures of LV diastolic dysfunction.nnnMETHODSnWe identified consecutive patients undergoing coronary CTA and transthoracic echocardiography who were assessed for diastolic function. CAD was evaluated on a per-patient, per-vessel, and per-segment basis for intraluminal diameter stenosis by using an 18-segment model (0 = none, 1 = 1%-49%, 2 = 50%-69%, and 3 = 70%-100%) and summed over segments to obtain overall coronary plaque burden (segment stenosis score [SSS]; maximum = 54). Transthoracic echocardiography evaluated mitral inflow E wave-to-A wave ratio, tissue Doppler early mitral annual tissue velocity axial excursion, stage of diastolic dysfunction, and LV dimensions and estimated LVEDP from the ratio of mitral inflow velocity to early mitral annular (medial) tissue velocity.nnnRESULTSnFour hundred seventy-eight patients (57% women; mean age, 57.9 ± 14.6 years; 24.9% prior CAD) comprised the study population. Increasing per-patient maximal coronary stenosis, number of vessels with obstructive stenosis, and SSS were associated with increased LVEDP. The prevalence of advanced diastolic dysfunction increased with greater number of obstructive vessels. In multivariable analyses, SSS was associated with increased LVEDP (0.8 mm Hg per tertile increase in SSS, 0.5-1.1; P < .001); reduced E axial excursion (-0.3; 95% confidence interval [CI], -0.5 to -0.1; P = .001), increased LV mass index (1.6 g/m(2) per tertile increase in SSS; P = .04), and increased relative wall thickness (0.005; 95% CI, 0.004-0.009; P = .03), with consistent relationships persisting even among persons with per-patient maximal stenosis <50% and LV ejection fraction ≥ 55%.nnnCONCLUSIONSnExtent and severity of obstructive as well as nonobstructive CAD by coronary CTA are associated with increased LVEDP and measures of diastolic dysfunction.

Abstract PD03-03: Pre-surgical Trial of Metformin in Overweight and Obese, Multi-ethnic Patients with Newly Diagnosed Breast Cancer

Background: Overweight or obese women with breast cancer (BC) have a higher risk of distant recurrence and death compared to normal weight women. There is increasing evidence that insulin significantly mediates these adverse clinical outcomes. Laboratory and population studies demonstrate that metformin offers a protective BC effect through reduction of serum insulin levels and direct modulation of cellular protein synthesis and growth through AMPK pathway signaling. Our aim is to assess the biologic impact of metformin on blood- and tumor-based markers on insulin, IGF and AMPK/mTOR pathway signaling, and/or proliferation in operable BC patients with a body mass index (BMI) ≥ 25 kg/m 2 . Methods: The study was an open-label pre-surgical trial with metformin 1500 mg PO per day (500 mg am/1000 mg pm) for 2–4 weeks prior to surgical resection in 35 overweight or obese patients with invasive BC (n = 25) or ductal carcinoma in situ (n = 10) and no history of diabetes. The primary endpoint was to assess a reduction in tumor proliferation. We have 80% power to detect a 30% decrease in Ki-67 in invasive BCs from baseline to post-metformin values (two-sample t-test, 0.05). Secondary endpoints include changes in BMI and insulin resistance markers, such as fasting serum insulin, lipid panel, glucose, leptin, and adiponectin. Tumor markers will be compared to untreated historical controls matched by age, BMI, and tumor characteristics. Results: Between Oct 2009 to Aug 2011, we screened 116 patients, enrolling 35 with newly diagnosed BC: 18/34 overweight (27.6: 25.1–29.7) and 16/34 obese (35.9: 30.5–46.4). Hispanic women made up 80% of the population (28/35). The median metformin duration was 22 days (1–64). All took metformin until the evening prior to surgery, except 2 (1 withdrew and 1 stopped early after surgery delay). More than half had a prior diagnosis of hypertension and a third had hypercholesterolemia. In the invasive BC cohort (n = 25), 19/25 (76%) were HR+/HER2−. The most common grade I-II included self-limiting diarrhea, flatulence, abdominal pain, fatigue, and anorexia. Grade III events included abdominal pain (n = 1) and diarrhea (n = 3). The change in blood markers are described in the table. Tumor Ki-67 (immunohistochemistry) and pathway signaling analyses (reverse protein microarray) are ongoing. Conclusions: Our study is unique to other pre-surgical metformin trials due to the enrichment of overweight/obese BC patients and the ethnically diverse population. We observed a significant decrease in serum cholesterol and leptin with metformin, and a trend toward lower insulin, HOMA, and adiponectin. No significant changes in glucose or IGFP-3 levels are noted. We are awaiting tumor-based biomarker evaluation. Pre-surgical trials can assess an agent9s biological effect prior to long-term intervention trials. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr PD03-03.

Abstract P3-08-12: Influence of a clinic-based survivorship intervention on dietary change and lifestyle recommendations among Hispanic and non-Hispanic women following adjuvant therapy for breast cancer

BACKGROUND: In 2006, the IOM released a report citing the importance of “survivorship plans” to improve quality-of-life. Little has been done to evaluate their efficacy with regard to uptake of dietary and lifestyle recommendations.nnMETHODS: Women with early-stage breast cancer were randomized within 6 weeks of completing adjuvant therapy to a survivorship intervention or a control group. Randomization was stratified by ethnicity and subjects were not aware that they were randomized. All subjects were provided the NCI publication, “Facing Forward: Life after Cancer Treatment.” The survivorship intervention group also met with a nurse (1 hour) and nutritionist (1 hour) to receive a treatment summary, surveillance and personalized lifestyle recommendations, based on guidelines from the American Cancer Society and American Institute for Cancer Research. At baseline, 3 and 6 months, both groups completed questionnaires on diet, lifestyle, and perceived health. Linear regression analyses adjusted for ethnicity evaluated the effects of the intervention on comprehension and uptake of lifestyle recommendations. Additional models were run to evaluate the interaction between intervention and ethnicity.nnRESULTS: Among 126 women (60 control group, 66 survivorship intervention) mean age was 54 yrs, 48% were Hispanic, and randomized groups were well-balanced by baseline characteristics. Of note, at baseline, compared to non-Hispanics, Hispanics reported lower SES, poorer knowledge of healthy lifestyle behaviors (e.g., diet, physical activity, weight, dietary supplements), lower intake of fruits and vegetables, less recreational physical activity, lower consumption of alcohol, and a lower overall health rating (all P<0.05). After adjusting for ethnicity, at month 3 the intervention group compared to the control group reported greater knowledge of how to eat a healthy diet (P = 0.047), greater knowledge of appropriate use of dietary supplements (P = 0.006), higher levels of physical activity (P = 0.03), and higher intake of fish (P = 0.005). At month 6, the only difference that persisted was greater knowledge of a healthy diet (P = 0.01). In models assessing an interaction between intervention condition and ethnicity, compared to Hispanics, the intervention had a stronger effect on increasing non-Hispanics’ belief that a healthy diet was important to prevent breast cancer recurrence (P = 0.02).nnCONCLUSIONS: Compared to only receiving written survivorship materials, a survivorship intervention that included written materials plus a 1 hour personalized lifestyle counseling session was associated with short-term increased knowledge of lifestyle recommendations, change in physical activity and change in dietary behaviors among a multi-ethnic group of breast cancer survivors. Behavioral effects were not observed beyond 3 months. A single 1 hour lifestyle consultation is likely not enough to achieve and maintain lifestyle recommendations. To facilitate long-term behavioral change among breast cancer survivors in the adjuvant setting, culturally competent behavioral interventions should be developed to increase knowledge of and the capabilities needed to meet lifestyle recommendations.nnCitation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P3-08-12.

P4-11-06: Uptake of Selective Estrogen Receptor Modulators and Other Breast Cancer Prevention Strategies among High-Risk Women Seen in a Breast Center.

Background: Selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, are FDA-approved for breast cancer (BC) risk reduction. However, uptake has been poor in the prevention setting, partly due to a lack of knowledge in the medical community about BC prevention and public misconceptions about the risks of SERMs. We assessed demographic and clinical factors that influence SERM uptake among high-risk women seen in an academic breast center, where specialized risk counseling is provided by a breast surgeon or medical oncologist. Methods: Potential subjects included high-risk women seen for an initial consultation by Breast Surgery or Medical Oncology. Eligibility for SERM use included a 5-year Gail risk ≥1.67%, lobular carcinoma in situ (LCIS), BRCA mutation carrier, or estrogen receptor (ER)-positive and/or progesterone receptor (PR)-positive ductal carcinoma in situ (DCIS). Demographic and BC risk factor data was collected from self-administered questionnaires. Clinical data, including prior/current SERM use, was abstracted from medical chart review. Differences in distribution of risk factors, between women who ever took a SERM and those who did not, were examined using chi-square statistics or Fisher9s exact test. Multivariable logistic regression models were used to calculate odds ratios (OR) and 95% confidence intervals using SERM use as the dependent variable. Results: Among 247 high-risk women enrolled between March 2007 and January 2011, median age 51 (17-82); White/Hispanic/Black/Asian (%): 55/32/7/6. 85% of women were undergoing annual mammography, 94% had a breast biopsy, 19% genetic testing, and 71% Medical Oncology referral. Among 181 (73%) women eligible for a SERM, Gail risk ≥1.67%/LCIS/DCIS/BRCA mutation (%): 35/22/39/3; 83 (46%) ever took a SERM, including 62 on tamoxifen and 21 on raloxifene. Early SERM discontinuation was only 7%. In multivariable analysis, significant predictors of SERM uptake included risk category (DCIS vs. Gail risk ≥1.67%/LCIS/BRCA mutation), higher income, higher body mass index (BMI), and referral to Medical Oncology. In terms of this high-risk population meeting American Cancer Society (ACS) behavioral guidelines for cancer prevention, 53% had a BMI Conclusions: Among high-risk women seen at a specialized breast center, application of clinical recommendations such as screening mammography, genetic testing, and SERM uptake were relatively high, suggesting that a comprehensive approach to the management of high-risk women is feasible. However, meeting ACS nutrition and physical activity guidelines for cancer prevention was limited, perhaps due to a lack of reimbursable staff to implement these guidelines. Breast cancer risk assessment and available interventions for prevention among high-risk women are underutilized in the U.S. Future studies should focus on the development and delivery of breast cancer prevention strategies. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-11-06.

Abstract P3-07-52: Identification of serum biomarkers associated with Akt inhibitor MK-2206-induced toxicity in a pre-surgical breast cancer (BC) trial

Background: The PI3K/Akt/mTOR pathway is an important oncogenic driver in BC. A major hurdle in clinical Akt inhibitor development has been dose-limiting toxicities, such as rash. To facilitate the risk assessment of Akt inhibitor associated toxicity, we hypothesize that circulating biomarkers can be identified in proteins secreted by the tumor or tumor microenvironment and systemic response after treatment. Exosomes are small membrane bound vesicles containing proteins, mRNA, miRNA, and lipids that are secreted from host cells and remain viable after long-term storage of blood. In this study, we focused on identifying biomarkers associated with drug rash from serum exosomes in BC patients treated with the Akt inhibitor MK-2206. Methods: In an open-label pre-surgical trial, 2 doses of weekly MK2206 were administered to patients (pts) with stage I-III invasive BC: first at day -9 and second at day -2 from surgery. Sera were collected before and after MK2206. 200 μL of serum was used to isolate total exosomes by precipitation and centrifugation, followed by trypsin digestion and multiplexing labeling analysis. The Orbitrap mass spectrometer was used to acquire LC-MS/MS data. 1,053 unique proteins were identified from the uniProt database. Maximum false discovery rate level (FDR) for predictive biomarkers was controlled at 26% (q Results: The study was discontinued after 12 pts were enrolled due to toxicity. Notably, an acneiform/maculopapular rash was observed in 5 pts. Unsupervised principal component analysis on the pre-MK-2206 specimens and the entire set of 1,053 proteins demonstrated that 4 of the 5 pts with rash formed a distinct cluster. 30 proteins were differentially expressed in pre-MK-2206 samples from pts who developed rash vs. no rash (q Conclusions: We demonstrated that mass spectrometry-based proteomic analysis of patient-derived serum exosomes is a promising approach to study drug-induced toxicity. We found significant changes of circulating proteins before and after MK-2206. Increased expression of different proteins involved in lipid metabolism appears to predict skin toxicity, commonly seen with PI3K/Akt pathway inhibitors. Since the PI3K/Akt signaling pathway plays a role in physiological regulation of lipid metabolism, lipid metabolic profiles of BC patients might be important for predicting the risk and controlling toxicity induced by Akt inhibitors. These toxicity-associated biomarkers should be validated and then assessed prospectively in clinical trials. Citation Format: Mundi PS, Chen E, Sparano J, Andreopoulou E, Taback B, Wiechmann L, Feldman S, Ananthakrishnan P, Hibshoosh H, Connolly E, Crew K, Maurer M, Hershman DL, Kalinsky K. Identification of serum biomarkers associated with Akt inhibitor MK-2206-induced toxicity in a pre-surgical breast cancer (BC) trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-07-52.

Abstract 693: A yeast synthetic lethal screen identifies a conserved interaction between PLK1 and CKS1b affecting cancer cell viability

The CKS1b gene is located on chromosome 1q21 and is frequently amplified in breast, lung and liver cancers. CKS1b codes for a conserved regulatory subunit of cyclin-CDK complexes that functions at multiple stages of cell cycle progression. We used a high throughput screening protocol to mimic cancer-related over-expression in Saccharomyces cerevisiae mutants to identify genes whose functions become essential only when CKS1 is over- expressed, a genetic interaction termed synthetic dosage lethality (SDL). Mutations in genes affecting the mitotic entry checkpoint and genes affecting mitotic exit are evident among the SDL interactions identified. The mitotic entry checkpoint controls the stability of the mitotic inhibitor Swe1 (Human WEE1), resulting in delayed mitosis when cell polarity is disrupted. Swe1 is a tyrosine kinase that inhibits the cyclin-dependent kinase (CDK) complex by phosphorylation of a conserved tyrosine-19 on Cdc28 (Human CDK1). We find that the SDL interaction between Cks1 and the mitotic entry checkpoint requires both Swe1 and the Cdc28 tyrosine-19 residue. The mitotic exit network is a signaling cascade that controls post-anaphase inhibition of CDK activity necessary for progression into G1. Since the polo-like kinase Cdc5 (Human PLK1) functions in both the mitotic entry and mitotic exit pathways, we investigated the effect of targeting PLK1 in breast cancers with varying expression of CKS1b. We analyzed published datasets and found that growth inhibition resulting from PLK1 knockdown was strongly correlated with increased CKS1b expression levels in breast cancer cell lines [Marcotte, R., Brown, K., Suarez, F., & Sayad, A. (2012). Cancer Discovery, 2:172]. We independently confirmed sensitivity to PLK1 knockdown in 8 breast cancer cell lines in which 3 of 4 sensitive lines had high CKS1b expression and 3 of 4 insensitive lines had low CKS1b expression. We modified CKS1b expression in hMEC cells and showed that increased expression enhanced apoptosis upon PLK1 knockdown while decreased CKS1b expression abrogated sensitivity. Thus identification of a yeast synthetic dosage lethal (SDL) interactions identifies a conserved interactions that may be targeted to kill cancer cells. Citation Format: Robert J. Reid, Xing Du, Ivana Sunjevaric, Vinayak Rayannavar, John Dittmar, Matthew Maurer, Rodney Rothstein. A yeast synthetic lethal screen identifies a conserved interaction between PLK1 and CKS1b affecting cancer cell viability. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 693. doi:10.1158/1538-7445.AM2015-693