Abstract: Older women with breast cancer remain under-represented in clinical trials. The Cancer and Leukemia Group B 49907 trial focused on women age 65 years and older. We previously reported the primary analysis after a median follow-up of 2.4 years. Standard adjuvant chemotherapy showed significant improvements in recurrence-free survival (RFS) and overall survival compared with capecitabine. We now update results at a median follow-up of 11.4 years. PATIENTS AND METHODS Patients age 65 years or older with early breast cancer were randomly assigned to either standard adjuvant chemotherapy (physician’s choice of either cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide and doxorubicin) or capecitabine. An adaptive Bayesian design was used to determine sample size and test noninferiority of capecitabine. The primary end point was RFS. RESULTS The design stopped accrual with 633 patients at its first sample size assessment. RFS remains significantly longer for patients treated with standard chemotherapy. At 10 years, in patients treated with standard chemotherapy versus capecitabine, the RFS rates were 56% and 50%, respectively (hazard ratio [HR], 0.80; P = .03); breast cancer–specific survival rates were 88% and 82%, respectively (HR, 0.62; P = .03); and overall survival rates were 62% and 56%, respectively (HR, 0.84; P = .16). With longer follow-up, standard chemotherapy remains superior to capecitabine among hormone receptor–negative patients (HR, 0.66; P = .02), but not among hormone receptor–positive patients (HR, 0.89; P = .43). Overall, 43.9% of patients have died (13.1% from breast cancer, 16.4% from causes other than breast cancer, and 14.1% from unknown causes). Second nonbreast cancers occurred in 14.1% of patients. CONCLUSION With longer follow-up, RFS remains superior for standard adjuvant chemotherapy versus capecitabine, especially in patients with hormone receptor–negative disease. Competing risks in this older population dilute overall survival benefits.

Abstract: Background: Older pts with BC receiving adjuvant tx are at increased risk of chemo tox; however, no BC-specific tool exists to quantify this risk. The Cancer and Aging Research Group (CARG) developed/validated a chemo tox score for older pts with all stages of solid tumor. The goals of this study were to: 1) build upon the CARG score by developing/validating CARG-BC (a BC specific adjuvant chemo tox score for older pts) and 2) evaluate its association with dose modifications, reduced relative dose intensity (RDI) and hospitalizations. Methods: 501 pts age ≥65 with stage I-III BC from 16 sites were accrued (300 development; 201 validation cohort). A pre-chemo assessment captured: CARG chemo tox score, BC tumor/tx variables, and additional geriatric assessment (GA) items. Grade 3-5 chemo tox by NCI CTCAE v 4.0 was captured. Univariate analysis identified chemo tox risk factors (p & lt;0.10) in addition to the CARG score which were used to develop a predictive model by best subset method; each risk factor was assigned a score, and summed to yield a total score (CARG-BC). Model performance was assessed by area under the ROC curves (AUC) of the development cohort, 10-fold internal validation, external validation, and goodness of fit. Results: Among 501 pts, 28 received non-standard regimens and were excluded, leaving 473 evaluable pts: 283 development and 190 validation cohort. The development cohort (median age 70; range 65-85) had Stage I (39%), II (41%), & III (20%) BC with 65% hormone positive, 24% triple negative, 27% Her2 positive; and 37% received an anthracycline. Grade 3-5 tox occurred in 46% (36% grade 3, 10% grade 4, 0.4% grade 5). The CARG score was significantly associated with grade 3-5 tox (p & lt;0.001; AUC 0.64). The addition of BC tumor/tx & GA variables (CARG-BC: see table) improved the AUC to 0.76 (95% CI, 0.70-0.82; goodness of fit p=0.28). The score ranged from 0-19, (low risk 0-5, mid risk 6-9, high risk 10+) and was significantly associated with grade 3-5 tox (p & lt;0.001) while KPS was not (p=0.20). The 10-fold internal validation AUC was 0.78. The external validation AUC (0.69) was not statistically different (p=0.15) from the development AUC. A higher CARG-BC score was associated with dose delay/reduction, chemo discontinuation, hospitalization, and RDI & lt;85% (all p-value & lt;0.001). Conclusions: We developed and validated a risk score (CARG-BC) which identifies an older pt's risk for adjuvant BC chemo tox and is associated with dose reduction, delay, reduced RDI, and hospitalization. This tool could be considered as a part of adjuvant tx decision-making. Chemo Tox Risk Score for BC (CARG-BC) Grade 3-5 Tox (%)ScoreCARG-Score: age, # of chemo drugs, dose, hemoglobin, creatinine clearance, hearing, falls, ability to walk 1 block and take meds, decreased social activitiesLow360Middle573High613StageI330II/III552Planned Tx Duration≤ 3 mo.330 & gt; 3 mo.584AnthracyclineNo380Yes591Liver FunctionNormal450Abnormal623Ability to Walk a MileNot limited370Limited613Someone to Provide AdviceMost of Time440None to Some of Time613 CARG-BC Risk ScoreLow210-5Middle456-9High7910+ Citation Format: Hurria A, Magnuson A, Gross CP, Tew WP, Klepin HD, Wildes TM, Muss HB, Dotan E, Freedman R, O'Connor T, Dale W, Cohen HJ, Katheria V, Arsenyan A, Levi A, Kim H, Sun C-L. Development and validation of a chemotherapy toxicity (Chemo Tox) risk score for older patients (Pts) with breast cancer (BC) receiving adjuvant/neoadjuvant treatment (Adjuvant Tx): A R01 and BCRF funded prospective multicenter study [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 GS6-04.

Abstract: Introduction: The most effective initial therapy for older adults with CLL has not yet been established due to the lack of comparison of chemoimmunotherapy (CIT) and targeted therapy with the Bruton's Tyrosine Kinase (BTK) inhibitor ibrutinib. CIT has been the gold standard since studies showing that addition of CD20 antibody to chemotherapy prolongs survival. Bendamustine plus rituximab (BR) is one standard, more aggressive CIT regimen for patients (pts) age 65 or older. While ibrutinib has been FDA approved for untreated CLL since 2016, it has only been compared to chlorambucil, which is relatively ineffective, and never before to aggressive CIT. Additionally, the benefit of the addition of rituximab to ibrutinib in this setting has not been prospectively studied in a phase 3 trial. As part of a randomized phase 3 trial, the Alliance sought to answer these important clinical questions. Pts and Methods: Alliance A041202 is a multicenter NCI National Clinical Trials Network phase 3 study comparing BR (Arm 1) with ibrutinib (Arm 2) and the combination of ibrutinib plus rituximab (Arm 3) to determine whether ibrutinib-containing regimens are superior to CIT in terms of PFS. Additionally, this study sought to determine if adding rituximab to ibrutinib would prolong PFS over ibrutinib alone. At time of progression, pts on Arm 1 could cross over to Arm 2. Eligible pts were those age ≥ 65 years with previously untreated, symptomatic CLL. Pts had a CrCl ≥ 40 mL/min, bilirubin ≤ 1.5 x ULN, and no significant life-limiting intercurrent illness or need for warfarin treatment. Pts were stratified based upon Rai stage, Zap-70 methylation performed centrally, and del(17)(p13.1) or del(11)(q22.3) by local interphase cytogenetics and were randomized 1:1:1 to each arm. With 166 pts per arm, the trial was powered to detect an improvement in 2-year PFS from 61% in Arm 1 to 75% in Arms 2 or 3 (HR=0.586) using two one-sided log-rank tests with type I error rate of 2.5% and 90% power. The Alliance Data and Safety Monitoring Board approved the data release after meeting the protocol-defined efficacy threshold at a planned interim analysis with a one-sided critical value of 0.001538. These data were locked July 2, 2018; updated results will be presented at the meeting. Results: Between 12/9/2013 and 5/16/2016, 547 pts were registered and randomized (Arms 1: 183, 2: 182, and 3: 182). Median age was 71 years and 67% of pts were men. High-risk Rai stage (stage III/IV) was seen in 54%, unmethylated Zap-70 in 53%, and del(17p) or del(11q) by local FISH in 28%. Local vs centralized FISH was performed for del(11q) and del(17p) with agreement between local and central results in 94% (Kappa=0.80) and 97% (Kappa=0.76) of pts, respectively. 525 (96%) pts were eligible and included in the primary PFS analysis (Arms 1: 176, 2: 178, and 3: 171). With median follow-up of 32 months (mo), median PFS was 41 mo in Arm 1 and has not been reached in Arms 2 or 3 (HR comparing Arm 2 to 1 is 0.40 with one-sided p & lt;0.0001; HR comparing Arm 3 to 1 is 0.41 with one-sided p & lt;0.0001; HR comparing Arm 3 to 2 is 1.01 with one-sided p=0.48). 2-year PFS estimates were 74%, 87% in 2, and 88% in Arms 1, 2, and 3 respectively. At this time, there are no significant differences in overall survival (OS) among arms (p=0.87), median OS has not been reached for any arm, and 2-year OS estimates were 95%, 90%, and 94% in Arms 1, 2, and 3, respectively. Adverse events (AEs) were compared among arms using Fisher's exact tests. Grade 3+ treatment-emergent AEs were seen in 428 of 537 evaluable pts with 61%, 41%, and 38% of pts experiencing Grade 3+ heme AEs (p & lt;0.0001) and 60%, 72%, and 71% of pts experiencing Grade 3+ non-heme AEs (p=0.03) in Arms 1, 2, and 3 respectively. Grade 5 AEs were seen in 5 (2.8%), 14 (7.8%), and 14 (7.7%) pts (p=0.07). Unexplained or unwitnessed death over the entire observation period was seen in 2 (1.1%), 7 (3.9%), and 4 (2.2%) pts (p=0.24) in Arms 1, 2, and 3 respectively. Conclusions: This international phase 3 trial demonstrates that ibrutinib produces superior PFS to standard CIT in older pts with CLL and justifies it as a standard of care treatment for pts age 65 and older. The addition of rituximab does not prolong PFS with ibrutinib. While ibrutinib represents a major therapeutic advance, toxicities and also cost justify future efforts to reduce the need for long-term continuous treatment. Support: K23CA178183, R01CA183444, U10CA180821, U10CA180882, U24CA196171, Clinicaltrials.gov identifier: NCT01886872 Figure. Figure. Disclosures Ding: Merck: Research Funding. Bartlett:Astra Zeneca: Research Funding; ImaginAB: Research Funding; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Bristol-Meyers Squibb: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Research Funding; Pharmacyclics: Research Funding; Affimed: Research Funding; Janssen: Research Funding; Novartis: Research Funding; Merck & Co: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Immune Design: Research Funding; Forty Seven: Research Funding; Novartis: Research Funding; Millennium: Research Funding. Brander:BeiGene: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; TG Therapeutics: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Genentech: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Novartis: Consultancy, Other: DSMB; AbbVie: Consultancy, Honoraria, Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; Pharmacyclics, an AbbVie Company: Consultancy, Honoraria, Research Funding; Teva: Consultancy, Honoraria; Acerta: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding; DTRM: Other: Institutional research funding for non investigator initiated clinical trial, Research Funding. Barr:AbbVie, Gilead: Consultancy. Parikh:Gilead: Honoraria; Pharmacyclics: Honoraria, Research Funding; MorphoSys: Research Funding; Janssen: Research Funding; AstraZeneca: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding. Coutre:Celgene: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; Gilead: Research Funding; Beigene: Consultancy; AbbVie: Consultancy, Research Funding. Lozanski:Novartis: Research Funding; BI: Research Funding; Genentech: Research Funding; Stem Line: Research Funding; Coulter: Research Funding; Beckman: Research Funding. Larson:Ariad/Takeda: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Erba:Amgen: Research Funding; Juno: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; MacroGenics: Consultancy; Juno: Research Funding; Janssen: Research Funding; Seattle Genetics: Consultancy, Research Funding; Janssen: Research Funding; Juno: Research Funding; Agios: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Incyte: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Novartis: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Incyte: Consultancy, Speakers Bureau; MacroGenics: Consultancy; Celgene: Consultancy, Speakers Bureau; Janssen: Research Funding; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Astellas: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; MacroGenics: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Juno: Research Funding; Janssen: Research Funding; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Astellas: Research Funding; Agios: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Amgen: Research Funding; Pfizer: Consultancy, Other: grant; Pfizer: Consultancy, Other: grant; Astellas: Research Funding; Amgen: Research Funding; Agios: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Pfizer: Consultancy, Other: grant; Jazz: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Jazz: Consultancy, Speakers Bureau; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Speakers Bureau; Immunogen: Consultancy, Research Funding; Takeda/Millenium: Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee; Celgene: Consultancy, Speakers Bureau; Takeda/Millenium: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Glycomimetics: Consultancy, Other: Chair, Data and Safety Monitoring Committee. Owen:Janssen: Honoraria, Research Funding; Celgene: Research Funding; AstraZeneca: Honoraria, Research Funding; Pharmacyclics: Research Funding; F. Hoffmann-La Roche Ltd: Honoraria, Research Funding; AbbVie: Research Funding; Merck: Honoraria; Teva: Honoraria. Abramson:Bayer: Consultancy; Novartis: Consultancy; Merck: Consultancy; Karyopharm: Consultancy; Seattle Genetics: Consultancy; Verastem: Consultancy; Humanigen: Consultancy; Juno Therapeutics: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Amgen: Consultancy.

Abstract: To determine if older patients with breast cancer have cognitive impairment before systemic therapy. Patients and Methods Participants were patients with newly diagnosed nonmetastatic breast cancer and matched friend or community controls age 〉 60 years without prior systemic treatment, dementia, or neurologic disease. Participants completed surveys and a 55-minute battery of 17 neuropsychological tests. Biospecimens were obtained for APOE genotyping, and clinical data were abstracted. Neuropsychological test scores were standardized using control means and standard deviations (SDs) and grouped into five domain z scores. Cognitive impairment was defined as any domain z score two SDs below or ≥ two z scores 1.5 SDs below the control mean. Multivariable analyses evaluated pretreatment differences considering age, race, education, and site; comparisons between patient cases also controlled for surgery. Results The 164 patient cases and 182 controls had similar neuropsychological domain scores. However, among patient cases, those with stage II to III cancers had lower executive function compared with those with stage 0 to I disease, after adjustment (P = .05). The odds of impairment were significantly higher among older, nonwhite, less educated women and those with greater comorbidity, after adjustment. Patient case or control status, anxiety, depression, fatigue, and surgery were not associated with impairment. However, there was an interaction between comorbidity and patient case or control status; comorbidity was strongly associated with impairment among patient cases (adjusted odds ratio, 8.77; 95% CI, 2.06 to 37.4; P = .003) but not among controls (P = .97). Only diabetes and cardiovascular disease were associated with impairment among patient cases. Conclusion There were no overall differences between patients with breast cancer and controls before systemic treatment, but there may be pretreatment cognitive impairment within subgroups of patient cases with greater tumor or comorbidity burden.

Abstract: Background: Older adults are less likely to be included in clinical trials leading to the approval of novel cancer treatments. The Institute of Medicine and ASCO have identified therapeutic phase II trials as a key research priority to increase the evidence base for older adults with cancer. While targeted therapies may represent a less toxic option for older patients, few trials have studied their tolerability and efficacy in older adults. Here, we present a phase II study (NCT01273610) of the combination of trastuzumab and lapatinib in older patients with HER2+ metastatic breast cancer (MBC), incorporating geriatric oncology principles in the study design. Methods: Patients age ≥ 60 years with MBC and any number of prior chemotherapy (CT) lines received trastuzumab (either 4mg/kg loading dose followed by 2mg/kg weekly or 8mg/kg followed by 6mg/kg q/3 weeks) plus lapatinib 1000 mg/m2 daily in 21-day cycles. Patients completed a pre-treatment geriatric assessment including measures of function, comorbidity, cognition, nutrition, and psychosocial status. A toxicity risk score developed for older adults receiving cytotoxic CT was calculated for each patient (Hurria et al. JCO 2011 & 2016). Relationships between tolerability (dose reductions and grade (G) ≥ 3 toxicity attributed to treatment) and risk score analyzed using a log2 transformation were assessed using generalized linear models, Student's t tests, and Fisher's exact test. Response rate (RR) and progression free survival (PFS) were evaluated. Results: 40 patients (mean age 72 [60-92]) were accrued from 04/11 to 05/15. 25% (n = 10) were ≥ 75 years of age. 65% of patients (n = 26) had HR+ tumors and 35% (n = 14) were receiving ≥ 3rd line treatment. Median number of cycles was 4 (0-28). RR was 23% (n = 9, 95% CI 11-38%; 1 complete, 8 partial). 23% (n = 9) achieved stable disease. PFS was 2.7 months (95% CI 2.5-12). Based on the toxicity risk score, 21% (n = 8), 54% (n = 21), and 26% (n = 10) were at low, intermediate, and high risk. 70% (n = 28) of patients had G ≥ 2 toxicities and 20% (n = 8) G ≥ 3 toxicities. G 2 and 3 diarrhea occurred in 28% (n = 11) and 5% (n = 2) respectively. 5% (n = 2) were hospitalized due to treatment-related toxicity. No G ≥ 3 cardiac toxicities were observed. 23% of patients (n = 9) had treatment delays, and 43% (n = 17) required a lapatinib dose reduction. The mean toxicity risk score was higher in patients who required dose reductions (Student's t: p = 0.02). No statistically significant relationship was found between toxicity risk scores and the presence of G ≥ 3 treatment toxicity (logistic regression: OR = 3.08, 95% CI [0.54, 21.2] , p = 0.22). Conclusions: Among older patients with MBC (79% at intermediate or high risk of G ≥ 3 cytotoxic CT toxicity), trastuzumab and lapatinib were well tolerated, with only 20% experiencing G3 toxicities. The toxicity risk score was not found to be significantly related with treatment toxicity, which may be explained by the very low incidence of G3 events. Patients with a low toxicity risk score were not likely to require a lapatinib dose reduction. Citation Format: O'Connor T, Soto-Perez-de-Celis E, Blanchard S, Chapman A, Kimmick G, Muss H, Luu T, Waisman JR, Li D, Mortimer J, Yuan Y, Somlo G, Stewart D, Katheria V, Levi A, Hurria A. Tolerability of the combination of lapatinib and trastuzumab in older patients with HER2 positive metastatic breast cancer [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P5-21-08.