Mayer, IA

PURPOSE Systematic integration of tobacco cessation treatment within cancer centers is needed to improve smoking cessation outcomes among cancer patients and survivors. The current study characterizes baseline rates of tobacco use, use of cessation support, and changes in tobacco use over time among 756 participants diagnosed with cancer and enrolled in 9 ECOG-ACRIN Cancer Research Group trials. MATERIALS AND METHODS Participants completed surveys at trial enrollment and at 3- and 6-month follow-ups. Descriptive statistics were used to characterize patient characteristics and selected items from the Cancer Patient Tobacco Use Questionnaire (C-TUQ). Generalized estimating equations were used to examine the time point effect on tobacco product use. RESULTS At baseline, 11% of participants (n = 740) currently smoked cigarettes. Among participants with data available at all time points (n = 443), prevalence of current smoking was stable over time, with 7.2% of participants (n = 32) reporting current smoking at baseline, 7.0% (n = 31) at the 3-month follow-up assessment, and 6.8% (n = 30) at the 6-month follow-up assessment. Most participants (n = 77/104) who smoked cigarettes within the year prior to their cancer diagnosis continued smoking after their diagnosis, and during (n = 44/72) and following completion (n = 30/46) of their treatment. Sixty-two percent of participants (n = 81) who were currently smoking at baseline reported using smoking cessation medication and 32.1% reported use of nonpharmacologic smoking cessation support since their cancer diagnosis. In longitudinal analyses, the odds of using cigarettes since their cancer diagnosis, 3-month follow-up, and 6-month follow-up was higher than the odds of using cigarettes for the past 30 days at baseline (odds ratio [OR] = 1.97, OR = 1.62, and OR = 1.50, respectively; all p s < .01). CONCLUSION Smoking persists over time among patients with cancer enrolled in therapeutic cancer trials. Findings highlight the importance of increasing access to integrated and longitudinal smoking cessation support.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. Metformin has been associated with lower cancer risk in epidemiologic and preclinical research. In the MA.32 randomized adjuvant breast cancer trial, metformin ( v placebo) did not affect invasive disease-free or overall survival. Here, we report metformin effects on the risk of new cancer. Between 2010 and 2013, 3,649 patients with breast cancer younger than 75 years without diabetes with high-risk T1-3, N0-3 M0 breast cancer (any estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2) were randomly assigned to metformin 850 mg orally twice a day or placebo twice a day for 5 years. New primary invasive cancers (outside the ipsilateral breast) developing as a first event were identified. Time to events was described by the competing risks method; two-sided likelihood ratio tests adjusting for age, BMI, smoking, and alcohol intake were used to compare metformin versus placebo arms. A total of 184 patients developed new invasive cancers: 102 metformin and 82 placebo, hazard ratio (HR), 1.25; 95% CI, 0.94 to 1.68; P = .13. These included 48 contralateral invasive breast cancers (27 metformin v 21 placebo), HR, 1.29; 95% CI, 0.72 to 2.27; P = .40 and 136 new nonbreast primary cancers (75 metformin v 61 placebo), HR, 1.24; 95% CI, 0.88 to 1.74; P = .21. Metformin did not reduce the risk of new cancer development in these nondiabetic patients with breast cancer.

Abstract Background: While cigarette smoking has declined among the U.S. general population, sale and use of non-cigarette alternative tobacco products (ATP; e.g., e-cigarettes, cigars) and dual use of cigarettes/ATPs are rising. Little is known about ATP use patterns in cancer survivors enrolled in clinical trials. We investigated prevalence of tobacco product use, and factors associated with past 30-day use, among patients with cancer in national trials. Methods: Cancer survivors (N = 756) enrolled in 9 ECOG-ACRIN clinical trials (2017–2021) completed a modified Cancer Patient Tobacco Use Questionnaire (C-TUQ) which assessed baseline cigarette and ATP use since cancer diagnosis and in the past 30 days. Results: Patients were on average 59 years old, 70% male, and the mean time since cancer diagnosis was 26 months. Since diagnosis, cigarettes (21%) were the most common tobacco product used, followed by smokeless tobacco use (5%), cigars (4%), and e-cigarettes (2%). In the past 30 days, 12% of patients reported smoking cigarettes, 4% cigars, 4% using smokeless tobacco, and 2% e-cigarettes. Since cancer diagnosis, 5.5% of the sample reported multiple tobacco product use, and 3.0% reported multiple product use in the past 30 days. Males (vs. females; OR 4.33; P = 0 &lt; 0.01) and individuals not living with another person who smokes (vs. living with; OR, 8.07; P = 0 &lt; 0.01) were more likely to use ATPs only versus cigarettes only in the past 30 days. Conclusions: Among patients with cancer, cigarettes were the most prevalent tobacco product reported. Impact: Regardless, ATPs and multiple tobacco product use should be routinely assessed in cancer care settings.

PURPOSE The PALLAS study investigated whether the addition of palbociclib, an oral CDK4/6 inhibitor, to adjuvant endocrine therapy (ET) improves invasive disease-free survival (iDFS) in early hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2–) breast cancer. In this analysis, we evaluated palbociclib exposure and discontinuation in PALLAS. METHODS Patients with stage II-III HR+, HER2– disease were randomly assigned to 2 years of palbociclib with adjuvant ET versus ET alone. The primary objective was to compare iDFS between arms. Continuous monitoring of toxicity, dose modifications, and early discontinuation was performed. Association of baseline covariates with time to palbociclib reduction and discontinuation was analyzed with multivariable competing risk models. Landmark and inverse probability weighted per-protocol analyses were performed to assess the impact of drug persistence and exposure on iDFS. RESULTS Of the 5,743 patient analysis population (2,840 initiating palbociclib), 1,199 (42.2%) stopped palbociclib before 2 years, the majority (772, 27.2%) for adverse effects, most commonly neutropenia and fatigue. Discontinuation of ET did not differ between arms. Discontinuations for non–protocol-defined reasons were greater in the first 3 months of palbociclib, and in the first calendar year of accrual, and declined over time. No significant relationship was seen between longer palbociclib duration or ≥ 70% exposure intensity and improved iDFS. In the weighted per-protocol analysis, no improvement in iDFS was observed in patients receiving palbociclib versus not (hazard ratio 0.89; 95% CI, 0.72 to 1.11). CONCLUSION Despite observed rates of discontinuation in PALLAS, analyses suggest that the lack of significant iDFS difference between arms was not directly related to inadequate palbociclib exposure. However, the discontinuation rate illustrates the challenge of introducing novel adjuvant treatments, and the need for interventions to improve persistence with oral cancer therapies.

PURPOSE Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor approved for advanced breast cancer. In the adjuvant setting, the potential value of adding palbociclib to endocrine therapy for hormone receptor–positive breast cancer has not been confirmed. PATIENTS AND METHODS In the prospective, randomized, phase III PALLAS trial, patients with hormone receptor–positive, human epidermal growth factor receptor 2–negative early breast cancer were randomly assigned to receive 2 years of palbociclib (125 mg orally once daily, days 1-21 of a 28-day cycle) with adjuvant endocrine therapy or adjuvant endocrine therapy alone (for at least 5 years). The primary end point of the study was invasive disease-free survival (iDFS); secondary end points were invasive breast cancer–free survival, distant recurrence-free survival, locoregional cancer-free survival, and overall survival. RESULTS Among 5,796 patients enrolled at 406 centers in 21 countries worldwide over 3 years, 5,761 were included in the intention-to-treat population. At the final protocol-defined analysis, at a median follow-up of 31 months, iDFS events occurred in 253 of 2,884 (8.8%) patients who received palbociclib plus endocrine therapy and in 263 of 2,877 (9.1%) patients who received endocrine therapy alone, with similar results between the two treatment groups (iDFS at 4 years: 84.2% v 84.5%; hazard ratio, 0.96; CI, 0.81 to 1.14; P = .65). No significant differences were observed for secondary time-to-event end points, and subgroup analyses did not show any differences by subgroup. There were no new safety signals for palbociclib in this trial. CONCLUSION At this final analysis of the PALLAS trial, the addition of adjuvant palbociclib to standard endocrine therapy did not improve outcomes over endocrine therapy alone in patients with early hormone receptor–positive breast cancer.

Abstract Background Circulating levels of cancer antigen (CA) 15–3, a tumor marker and regulator of cellular metabolism, were reduced by metformin in a nonrandomized neoadjuvant study. We examined the effects of metformin (vs placebo) on CA 15–3 in participants of MA.32, a phase III randomized trial in early-stage breast cancer. Methods A total of 3649 patients with T1-3, N0-3, M0 breast cancer were randomly assigned; pretreatment and 6-month on-treatment fasting plasma were centrally assayed for CA 15–3. Genomic DNA was analyzed for the rs11212617 single nucleotide polymorphism. Absolute and relative change of CA 15–3 (metformin vs placebo) were compared using Wilcoxon rank and t tests. Regression models adjusted for baseline differences and assessed key interactions. All statistical tests were 2-sided. Results Mean (SD) age was 52.4 (10.0) years. The majority of patients had T2/3, node-positive, hormone receptor–positive, HER2-negative breast cancer treated with (neo)adjuvant chemotherapy and hormone therapy. Mean (SD) baseline CA 15–3 was 17.7 (7.6) and 18.0 (8.1 U/mL). At 6 months, CA 15–3 was statistically significantly reduced in metformin vs placebo arms (absolute geometric mean reduction in CA 15–3 = 7.7% vs 2.0%, P &lt; .001; relative metformin: placebo level of CA 15–3 [adjusted for age, baseline body mass index, and baseline CA 15–3] = 0.94, 95% confidence interval = 0.92 to 0.96). This reduction was independent of tumor characteristics, perioperative systemic therapy, baseline body mass index, insulin, and the single nucleotide polymorphism status (all Ps &gt; .11). Conclusions Our observation that metformin reduces CA 15–3 by approximately 6% was corroborated in a large placebo-controlled randomized trial. The clinical implications of this reduction in CA 15–3 will be explored in upcoming efficacy analyses of breast cancer outcomes in MA.32.

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 (&gt;2 cm vs. &lt;=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 (&lt;/=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&lt;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: 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 &lt; 11 were assigned to endocrine therapy alone and with a high RS &gt; 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 &gt; 25, and 1639 (15.9%) had a low RS of &lt; 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 &lt;11. The characteristics of the low risk registry population are as follows: age 50 or less (27%), 51-60 (35%), &gt; 60 (39%); tumor size &lt; 1 cm (8%), 1-2 cm (61%), &gt; 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 &lt; 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 &gt;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]: &lt;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.