Dees, EC

Abstract Purpose: Statins may mediate suppression of molecular pathways conferring benefit in cancer. Statins have shown anti-tumor effects in preclinical studies and have been associated with decreased recurrence and improved disease-specific survival. While designed to target cholesterol biosynthesis, statins can also have liver, bone and brain effects. We collected data on statin use in the S0307 adjuvant bisphosphonate trial to test the hypothesis that statin use may decrease risk of recurrence to liver, bone and brain as well as second primary (contralateral) breast cancers, and may act synergistically with bisphosphonates to decrease the risk of recurrence to bone. Patients and Methods: In S0307, 6097 patients diagnosed with Stage I-III breast cancer who had undergone surgery and were receiving adjuvant systemic therapy were randomized to receive zoledronic acid, clodronate, or ibandronate for 3 years. No significant difference was found in disease-free survival (DFS) among the 3 groups, including a sub-analysis of patients > age 55. Statin use was infrequent in younger women in S0307, consequently we analyzed statin use in those > age 55. Cox proportional hazard models were used to determine which variables were independently associated with DFS and to estimate hazard ratios (HR) and 95% confidence intervals (CI). Results: Among women aged ≥ 55 years, 684 (27%) reported taking a statin at baseline and 1,848 did not. Both groups were similar in terms of hormone receptor and HER2 status (p = 0.82). Median age in the statin group was 64.3 versus 61.0 years in the no statin group, mean BMI 31.2 v. 29.5, mean tumor size 2.1cm v. 2.3cm, negative lymph nodes 60% v. 54%, Stage I disease 47% v. 36%, and receipt of chemotherapy 62% v. 71% (all p < 0.01). In the statin group, 122 (17.8%) experienced a DFS event compared to 313 (16.9%) in the no statin group (HR 1.18, CI 0.95-1.46). No difference was observed by statin use in overall recurrence (p=0.28), distant recurrence (p=0.64), or recurrences to the bone (p=0.64), liver (p=0.38) or brain (p=0.65) at initial recurrence. There was no synergy between statin use and specific bisphosphonates. Recurrence and statin useOutcomeGroup 1: On stan at baseline n=684Group 2: No statin at baseline n=1848DFS events122 (17.8%)313 (16.9%)Died without recurrence51 7.5%)97 (5.2%)Recurrence71 (10.4%)216 (11.7%)Contralateral breast cancer9 (1.3%)17 (0.9%)Distant recurrence48 (7%)157 (8.5%)Bone as 1st site of distant recurrence (% distant recurrence)31 (65%)76 (48%)Liver as 1st site of distant recurrence (% distant recurrence)6 (13%)24 (16%)Brain/CNS as 1st site of distant recurrence (% distant recurrence)5 (10%)17 (11%) Conclusions: We found no evidence that statins reduce risk of second primary breast cancers or distant metastases among post-menopausal women with early-stage breast cancer. Despite promising preclinical data, they did not appear to act in synergy with a specific bisphosphonate. Though women in the statin group had less advanced disease at study entry, statin use was not associated with improved DFS. Results are limited by lack of information about type of statin used, adherence, or initiation of statin in control group. Citation Format: Kizub D, Miao J, Stopeck A, Thompson P, Paterson AH, Clemons M, Dees EC, Ingle JN, Falkson CI, Barlow W, Hortobagyi GN, Gralow JR. Statin use, site of recurrence, and survival among post-menopausal women taking bisphosphonates as adjuvant therapy for breast cancer (SWOG S0307) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-17-03.

Abstract Background: Black race is associated with worse outcomes in localized hormone receptor (HR)-positive breast cancer in population-based and in clinical trial cohorts, whether using self-identified race (Albain et al. JNCI 2009 [PMID: 19584328; Sparano et al. JNCI 2012 [PMID: 22250182) or genetically-identified race (Schneider et al. J Precision Oncol 2017 [PMID: 29333527]). This disparity persists after adjustment for treatment delivery parameters (Hershman et al. JCO 2009 [PMID:19307504]). We evaluated clinicopathologic characteristics, treatment delivered and clinical outcomes in the Trial Assigning Individualized Options for Treatment (TAILORx) by race and ethnicity (Sparano et al. NEJM 2018 [PMID: 29860917]). Methods: The analysis included 9719 evaluable TAILORx participants. The association between clinical outcomes and race (white, black, Asian, other/unknown) and ethnicity (Hispanic vs. non-Hispanic) was examined, including invasive disease-free survival (iDFS), distant relapse-free interval (DRFI), relapse-free interval (RFI), and overall survival (OS). Proportional hazards models were fit including age (5 categories), tumor size (>2 cm vs. <=2 cm), histologic grade (high vs. medium vs. low vs. unknown), continuous recurrence score (RS), race, and ethnicity in the overall population and randomized treatment arms in the RS 11-25 cohort. Results: The study population included 8189 (84%) whites, 693 (7%) blacks, 405 (4%) Asians, and 432 (4%) with other/unknown race. Regarding ethnicity, 7635 (79%) were non-Hispanic, 889 (9%) Hispanic, and 1195 (12%) unknown. There was no significant difference in RS distribution (p=0.22) in blacks compared with whites, or in median (17 vs. 17) or mean RS (19.1 vs. 18.2). There was likewise no difference in Hispanic vs. non-Hispanic ethnicity for RS distribution (p=0.72) or median (17 vs. 17) or mean RS (18.5 vs. 18.0). Black race (39% vs. 30%) and Hispanic ethnicity (39% vs. 30%) were both associated with younger age (</=50 years) at diagnosis. The use and type of adjuvant chemotherapy and endocrine therapy, and duration of endocrine therapy, were similar in black (vs. white) and Hispanic (vs. non-Hispanic) populations. In proportional hazards models, black race (compared with white race) was associated with worse clinical outcomes in the entire population and in those with a RS 11-25 (see table). Hispanic ethnicity was generally associated with better outcomes (compared with non-Hispanic ethnicity). For the cohort with a RS of 11-25, there was no evidence for chemotherapy benefit for any racial or ethnic group. Race (black vs.white) and clinical outcomes in proportional hazards modelsClinical endpointEntire Population (N=693 black) Hazard ratio for eventRS 11-25 (N=471 black) Hazard ratio for eveniDFS1.33 (p=0.005)1.49 (p=0.001)DRFI1.21 (p=0.28)1.60 (p=0.02)RFI1.39 (p=0.02)1.80 (p<0.001)OS1.52 (p=0.005)1.67 (p=0.003 Conclusions: In patients eligible and selected for participation in TAILORx, black women had worse clinical outcomes despite similar 21-gene assay RS results and comparable systemic therapy. This adds to an emerging body of evidence suggesting a biologic basis or other factors contributing to racial disparities in HR-positive breast cancer that requires further evaluation. Citation Format: Albain K, Gray RJ, Sparano JA, Makower DF, Pritchard KI, Hayes DF, Geyer, Jr. CE, Dees EC, Goetz MP, Olson, Jr. JA, Lively T, Badve SS, Saphner TJ, Wagner LI, Whelan TJ, Ellis MJ, Paik S, Wood WC, Ravdin PM, Keane MM, Gomez HL, Reddy PS, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Berenberg JL, Abrams J, Sledge, Jr. GW. Race, ethnicity and clinical outcomes in hormone receptor-positive, HER2-negative, node-negative breast cancer: results from the TAILORx trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS4-07.

Abstract Background: Abemaciclib, a small molecule inhibitor of CDK4 and CDK6, induces G1 cell cycle arrest in Rb-proficient human cancers.1 The clinical safety profile of abemaciclib enables continuous oral dosing to achieve sustained target inhibition, resulting in single-agent antitumor activity against multiple human cancers. The drug also reaches relevant concentrations in the central nervous system and, in patients taking the drug orally, can be detected in the cerebrospinal fluid.2 For women with previously treated hormone receptor positive (HR+) metastatic breast cancer (MBC), abemaciclib as a single agent achieved a six-month clinical benefit rate of 61.1% and an objective response rate of 33.3%.3 Clinical trials investigating abemaciclib combined with fulvestrant4 or aromatase inhibitors5 have led to randomized Phase 3 studies for women with HR+ breast cancer.6,7 Methods: This Phase 1b study (NCT02057133) with multiple cohorts evaluates safety and tolerability of abemaciclib combined with endocrine or HER2-targeted therapies for MBC. Secondary objectives include pharmacokinetics (PK) and antitumor activity of abemaciclib when given in combination with other therapies. Cohorts were opened to enrollment sequentially. Patients with HR+ HER2 negative MBC received abemaciclib orally every 12 hours (Q12H) in combination with the following standard therapies daily until progression: letrozole (Part A), anastrozole (Part B), tamoxifen (Part C), exemestane (Part D), or exemestane plus everolimus (Part E). Patients with HER2 positive MBC received abemaciclib orally Q12H in combination with trastuzumab every 21 days until progression (Part F). Adverse events (AEs) were graded by NCI CTCAE v4.0 and tumor response was assessed radiographically using RECIST v1.1. Results: Abemaciclib has been combined with multiple targeted therapies for the treatment of women with MBC. We previously reported safety and early efficacy results for the combinations of abemaciclib with letrozole, anastrozole, tamoxifen, exemestane, and exemestane plus everolimus.5 Due to limited follow-up at that time, the efficacy results were not mature. Safety, PK, and efficacy results with approximately 6 months of additional follow-up will be reported across all parts of the study. The most common treatment-emergent AEs include effects on the gastrointestinal and hematopoietic systems. Consistent with previously reported results for both single-agent abemaciclib and the combination of abemaciclib with fulvestrant, tumor responses have been observed among women receiving abemaciclib in combination with targeted therapies for MBC. Conclusions: This study for women with MBC demonstrates the potential for abemaciclib to be combined with therapies targeting specific signaling pathways. References: 1Gelbert et al. Invest New Drugs. 2014;32(5):825-37. 2Shapiro et al. J Clin Oncol 31, 2013 (suppl; abstr 2500). 3Tolaney et al. SABCS 2014: Abstract 763. 4Patnaik et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 534). 5Tolaney et al. J Clin Oncol 33, 2015 (suppl; abstr 522). 6Llombart et al. SABCS 2014: OT1-1-07 (MONARCH 2, NCT02107703). 7Goetz et al. J Clin Oncol 33, 2015 (suppl; abstr TPS624) (MONARCH 3, NCT02246621). Citation Format: Goetz MP, Beeram M, Beck T, Conlin AK, Dees EC, Dickler MN, Helsten TL, Conkling PR, Edenfield WJ, Richards DA, Turner PK, Cai N, Chan EM, Pant S, Becerra CH, Kalinsky K, Puhalla SL, Rexer BN, Burris HA, Tolaney SM. Abemaciclib, an inhibitor of CDK4 and CDK6, combined with endocrine and HER2-targeted therapies for women with metastatic breast cancer. [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 P4-13-25.

Abstract Background: The Trial Assigning Individualized Options for Treatment (TAILORx) is a prospective trial evaluating the role of endocrine therapy or chemoendocrine therapy in patients 18-75 years of age with estrogen receptor (ER)-positive, HER2-negative breast cancer, a primary tumor between 0.6-5.0 cm, and negative axillary nodes, a population for whom chemotherapy is typically recommended or least considered based on National Comprehensive Cancer Center Network (NCCN) guidelines. Methods: The trial was designed to demonstrate non-inferiority of endocrine therapy compared with chemoendocrine therapy in the randomized group with an Oncotype DX Recurrence Score (RS) of 11-25. Patients with a low RS < 11 were assigned to endocrine therapy alone and with a high RS > 25 assigned to chemoendocrine therapy, and both groups were followed in a prospective registry. The definition of an intermediate RS differed in this trial (RS 11-25) from the original reports (RS 18-30) in order to reduce the risk of chemotherapy undertreatment in patients with a mid-range or low RS (Sparano & Paik. J Clin Oncol 2008; 26:721-728). Results: The trial enrolled 10,273 patients between April 2006 and October 2010, of whom 6907 patients (67.2%) had a mid-range RS of 11-25, 1737 (16.9%) had a high RS > 25, and 1639 (15.9%) had a low RS of < 11. At the fourth planned interim analysis, the ECOG-ACRIN data monitoring committee recommended that the study continue as planned for the randomized group with a RS 11-25, and that the results be released to the investigators for the low risk group with a RS <11. The characteristics of the low risk registry population are as follows: age 50 or less (27%), 51-60 (35%), > 60 (39%); tumor size < 1 cm (8%), 1-2 cm (61%), > 2 cm (31%); histologic grade low (34%), intermediate (59%), high (7%); breast conservation (68%) or mastectomy (32%). Initial endocrine therapy included tamoxifen in 35%, aromatase inhibitors in 59%, ovarian function suppression in 3%, and unspecified therapy in 3%; 5 patients received adjuvant chemotherapy (1 of whom relapsed). Five-year rates (and 95% confidence intervals [CI]) for low RS group were 99.2% (98.5, 99.6%) for distant relapse free interval, 98.5% (97.7, 99.1%) for relapse-free interval, 93.7% (92.2, 94.9%) for invasive disease free survival, and 98.2% (97.3, 98.7%) for overall survival. Information regarding ER, PR, and HER2 RNA expression will be presented. Conclusions: Despite meeting guidelines for recommending or at least considering adjuvant chemotherapy based on classical clinicopathologic features, the risk of recurrence was very low at 5 years in patients with ER-positive, HER2-negative, axillary node-negative breast cancer and a low RS of < 11 treated with endocrine therapy alone without chemotherapy. Citation Format: Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, Geyer Jr CE, Dees EC, Perez EA, Olson Jr JA, Zujweski J, Keane MM, Gomez Moreno HL, Reddi RP, Goggins TF, Mayer IA, Brufsky AM, Toppmeyer DL, Kaklamani VG, Atkins JN, Berenberg JL, Sledge Jr GW. Prospective trial of endocrine therapy alone in patients with estrogen receptor positive, HER2-negative, node-negative breast cancer: Results of the TAILORx low risk registry. [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 P2-08-01.

Abstract Background We evaluated the safety and efficacy of L+T in pts with 0–2 prior lines of chemotherapy (CT) for HER2+ MBC. In the context of this phase II trial, we evaluated metabolic response by FDG-PET and explored the relationship between metabolic response and clinical outcomes. Methods: Pts with measurable, HER2+ MBC were eligible. Cohort 1: No prior T, L, or CT +T for MBC, and >1 yr from adjuvant T, if received. Cohort 2: 1–2 prior lines of CT for MBC, including T, or relapse within 1 yr of adjuvant T. Pts received L 1,000 mg QD + T (2 mg/kg weekly or 6 mg/kg Q3W). Staging studies were done with CT or MRI at baseline (BL) and every 2 cycles (1 cycle=4 weeks [wks]). Objective response was assessed by local investigator according to RECIST 1.0. FDG-PET/CT was performed at BL, Wk 1, and Wk 8 per NCI guidelines. Central quality assurance, review, and analysis were performed on FDG-PET studies. Up to 5 target lesions were identified on BL FDG-PET images based on hypermetabolic uptake. Percent change in the summed maximum standardized uptake value (SUVmax) of target lesions was calculated at Wk 1 or Wk 8, compared to BL. Metabolic response was assessed according to EORTC criteria for % change in SUVmax (progressive disease [PD]: ≥25% increase; partial response [PR]: ≥25% decrease; stable disease [SD]: <25% change). Metabolic response at Wk 1 was compared to Wk 8 as well as to clinical outcome, including objective response, clinical benefit, and progression-free survival (PFS). Results: 87 pts were registered to the study. Of these, one pt did not begin protocol therapy and one pt did not have MBC on further testing, and are not included. 81/85 pts had FDG-PET data at Wk 1; 75/85 had data at Wk 8. Metabolic PR at Wk 1 was observed in 28/39 (72%) pts in Cohort 1 and 20/42 (48%) pts in Cohort 2. Metabolic PR at Wk 8 was observed in 27/34 (79%) pts in Cohort 1 and 18/41 (44%) pts in Cohort 2. Wk 1 and Wk 8 metabolic responses were similar. In cohort 1, 18/28 (64%) pts who achieved Wk 1 metabolic PR had clinical benefit by RECIST. Of pts with Wk 1 metabolic SD, 2/9 (22%) had clinical benefit. In cohort 2, 9/20 (45%) pts who achieved Wk 1 metabolic PR had clinical benefit; 5/22 (23%) who achieved Week 1 metabolic SD had clinical benefit. Exploratory analysis of progression-free survival (PFS) showed that pts in Cohort 1 who achieved Wk 1 metabolic PR experienced a median PFS of 9.3 months ([mos]; 95% CI 5.6−22.3); for pts with metabolic SD, median PFS was 1.9 mos (95% CI 0.8−5.5). For pts in Cohort 2, Wk 1 metabolic PR was associated with median PFS of 5.6 mos (95% CI 3.7−7.8), whereas for pts with metabolic SD, median PFS was 3.7 mos (95% CI 1.8−5.5). Conclusions: L+T is associated with a high rate of early and sustained metabolic response by FDG-PET. Exploratory analyses suggest that metabolic PR may be associated with clinical benefit and longer PFS. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-09-07.