Sparano, Joseph A.

Abstract Purpose: CD4 T-cell immunity is associated with improved survival in patients with breast cancer. We previously reported a phase I trial evaluating a folate receptor alpha (FRα) vaccine administered with cyclophosphamide (CP), demonstrating excellent safety and immunogenicity. To simplify the vaccine strategy for ease of use, we report here the results of a randomized phase II trial evaluating a lower vaccine dose alongside the original dose, administered with or without CP pretreatment. Patients and Methods: Patients with triple-negative breast cancer who completed all systemic and local therapies were assigned to receive either low-dose (825 μg) or high-dose (2.5 mg) vaccine peptides plus GM-CSF in six 4-week cycles, with or without CP prior to vaccination. Safety was monitored, and immunogenicity was evaluated before and after vaccination. Results: A total of 80 patients were dosed with vaccine, and 58 patients were evaluable for immunogenicity. Vaccination was well tolerated and elicited immunity in 83% of patients. Levels of FRα-specific T cells were high, persistent, and comparable with T-cell levels against tetanus toxoid. No differences in immunity were observed between the two doses. CP pretreatment also did not affect the immune responses. Recurrences occurred in eight evaluable patients and were unrelated to the treatment arm. No patients died during the study because of their disease. Conclusions: The reduced-dose FRα vaccine is as effective as the original dose and does not require CP to generate maximal immunity. These findings may inform the design of trials testing efficacy in triple-negative breast cancer or other cancers.

Abstract Purpose: Aromatase inhibitor (AI)–associated musculoskeletal symptoms (AIMSS) are common and frequently lead to AI discontinuation. SNPs in candidate genes have been associated with AIMSS and AI discontinuation. E1Z11 is a prospective cohort study designed to validate the association between 10 SNPs and AI discontinuation due to AIMSS. Patients and Methods: Postmenopausal women with stage I to III hormone receptor–positive breast cancer received anastrozole 1 mg daily and completed patient-reported outcome measures to assess AIMSS (Stanford Health Assessment Questionnaire) at baseline, 3, 6, 9, and 12 months. We estimated that 40% of participants would develop AIMSS and 25% would discontinue AI treatment within 12 months. Enrollment of 1,000 women with a fixed number per racial stratum provided 80% power to detect an effect size of 1.5 to 4. SNPs were found in ESR1 (rs2234693, rs2347868, and rs9340835), CYP19A1 (rs1062033 and rs4646), TCL1A (rs11849538, rs2369049, rs7158782, and rs7159713), and HTR2A (rs2296972). Results: Of the 970 evaluable women, 43% developed AIMSS and 12% discontinued AI therapy within 12 months. Although more Black and Asian women developed AIMSS than White women (49% vs. 39%, P = 0.017; 50% vs. 39%, P = 0.004, respectively), the AI discontinuation rates were similar across groups. None of the SNPs were significantly associated with AIMSS or AI discontinuation in the overall population or in distinct cohorts. The OR for rs2296972 (HTR2A) approached significance for developing AIMSS. Conclusions: We were unable to prospectively validate candidate SNPs previously associated with AI discontinuation due to AIMSS. Future analyses will explore additional genetic markers, patient-reported outcome predictors of AIMSS, and differences by race.

AbstractBackgroundPatient‐reported outcomes (PROs) are a better tool for evaluating the experiences of patients who have symptomatic, treatment‐associated adverse events (AEs) compared with clinician‐rated AEs. The authors present PROs assessing health‐related quality of life (HRQoL) and treatment‐related neurotoxicity for adjuvant capecitabine versus platinum on the Eastern Cooperative Oncology Group‐American College of Radiology Imaging Network (ECOG‐ACRIN) EA1131 trial (ClinicalTrials.gov identifier NCT02445391).MethodsParticipants completed the National Comprehensive Cancer Network Functional Assessment of Cancer Therapy–Breast Cancer Symptom Index (NFBSI‐16) and the Functional Assessment of Cancer Therapy–Gynecologic Oncology Group neurotoxicity subscale (platinum arm only) at baseline, cycle 3 day 1 (C3D1), 6 months, and 15 months. Because of early termination, power was insufficient to test the hypothesis that HRQoL, as assessed by the NFBSI‐16 treatment side‐effect (TSE) subscale, would be better at 6 and 15 months in the capecitabine arm; all analyses were exploratory. Means were compared by using t‐tests or the Wilcoxon rank‐sum test, and proportions were compared by using the χ2 test.ResultsTwo hundred ninety‐six of 330 eligible patients provided PROs. The mean NFBSI‐16 TSE subscale score was lower for the platinum arm at baseline (p = .02; absolute difference, 0.6 points) and for the capecitabine arm at C3D1 (p = .04; absolute difference, 0.5 points), but it did not differ at other times. The mean change in TSE subscale scores differed between the arms from baseline to C3D1 (platinum arm, 0.15; capecitabine arm, −0.72; p = .03), but not from baseline to later time points. The mean decline in Functional Assessment of Cancer Therapy–Gynecologic Oncology Group neurotoxicity subscale scores exceeded the minimal meaningful change (1.38 points) from baseline to each subsequent time point (all p < .05).ConclusionsDespite the similar frequency of clinician‐rated AEs, PROs identified greater on‐treatment symptom burden with capecitabine and complemented clinician‐rated AEs by characterizing patients’ experiences during chemotherapy.

Abstract Background: Late recurrence of breast cancer after 5 years accounts for about 50% of recurrences in hormone receptor (HR)-positive early breast cancer (EBC). TAILORx established non-inferiority of adjuvant endocrine therapy (ET) given for at least 5 years to chemotherapy plus ET (CET) in EBC and a 21-gene recurrence score (RS) of 11-25, although there was some chemotherapy benefit in women Methods: Eligibility criteria included women 18-75 years with HR-positive, HER2-negative, T1b-T2N0 EBC who agreed to have CT assigned or randomized based on the RS assay. The primary endpoint was invasive disease-free survival (iDFS) in the RS 11-25 group. The “primary analysis” refers to the original prespecified analysis for the primary IDFS endpoint (836 IDFS events at full information in the RS 11-25 group) after a median of 7.5 years. The “updated analysis” was performed after a median followup of 11.0 and 10.4 years in the randomized and overall populations, respectively. Results:10,253 eligible women enrolled between 4/7/06-10/6/10.The updated analysis includes substantially more events that the primary analysis, including IDFS events (1819 vs. 1210), distant recurrences (561 vs. 384), locoregional +/- distant recurrences (764 vs. 543), and deaths (910 vs. 499). The table provides 5 and 12-year event rates (and standard errors) for all arms, and comparisons of the randomized arms. The primary trial conclusions remain unchanged: ET was non-inferior to CET in the randomized group with a RS 11-25. Although recurrence occurred in &lt; 10% by 12 years for a RS 0-25, late recurrence events beyond 5 years exceeded earlier recurrence. Non-recurrence events occurred in about 13% at 12 years (~1%/year), contributing substantially to the IDFS rates. For women Conclusions: The current updated analysis confirms findings from the original primary analysis that ET is non-inferior to CET in HR-positive, HER2-negative, node-negative EBC and a RS 11-25. As in the original primary analysis, the subgroup of women Citation Format: Joseph Sparano, Robert J. Gray, Della Makower, Kathy S. Albain, Daniel F. Hayes, Charles Geyer, Elizabeth Dees, Matthew P. Goetz, John A. Olson Jr, Tracy G. Lively, Sunil Badve, Thomas Saphner, Lynne I. Wagner, Timothy Whelan, Virginia Kaklamani, George Sledge. Trial Assigning Individualized Options for Treatment (TAILORx): An Update Including 12-Year Event Rates [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-05.

12094 Background: The Functional Assessment of Cancer Therapy patient-reported outcomes (PRO) item GP5 (“I am bothered by side effects of treatment”) estimates treatment tolerability. We aimed to extend our previous finding that GP5 predicts early aromatase inhibitor (AI) discontinuation (E1Z03, 96% White) in the racially diverse E1Z11 trial cohort. Methods: E1Z11 was coordinated by the ECOG-ACRIN NCI Community Oncology Research Program (NCORP) Research Base. Postmenopausal women initiating anastrozole per clinical care for ER+ stage I-III breast cancer with a pain score 0-3/10 and no rheumatologic comorbidities were eligible. Accrual of a racially diverse cohort of 1,000 women, including Black and Asian women, was planned. GP5 was administered prior to initiating anastrozole (trial baseline) and at 3, 6, 9 and 12 months. GP5 was scored on a 5-point Likert scale from 0 (not at all) to 4 (very much) and dichotomized as no/little treatment bother (0/1) or moderate/high treatment bother (2-4), consistent with previous analyses. A univariate Cox proportional hazards model estimated baseline GP5’s association with treatment duration via hazard ratio (HR). Early treatment discontinuation status was defined as treatment duration < 12 months with discontinuation not attributed to disease progression or death (n = 4), consistent with previous analyses. Results: 1,046 women enrolled from 6/2013-10/2018 (640 White, 201 Black, 205 Asian), including 590 (56%) from NCORP Community or Minority/Underserved Sites. Approximately 10% (100/987 with GP5 data) reported moderate/high treatment bother prior to initiating anastrozole. Anastrozole discontinuation rate at 1-year was 26.2% overall; it was lower among women with no/little treatment bother (25.7%, GP5 = 0-1) compared to moderate/high treatment bother prior to initiating anastrozole (34.7%, GP5 = 2-4; HR = 1.50, 95% confidence interval [CI]:1.04-2.15, p = 0.027). Subgroup analyses by racial cohort showed a similar predictive effect of GP5 in the White (n = 606, HR = 1.76, 95% CI: 1.12-2.77, p = 0.014) and Black (n = 184, HR = 1.85, 95% CI: 0.92-3.71, p = 0.079) cohorts, but not in the Asian cohort (n = 197, HR = 0.40, 95% CI: 0.10-1.62, p = 0.20). Conclusions: Moderate/high treatment bother prior to starting anastrozole was observed in 10% of patients and associated with a higher risk of early discontinuation, except in Asian patients. Our findings support the presence of a treatment tolerability threshold which can be compromised by pre-treatment burden. Treatment tolerability may also be influenced by cultural and genetic factors, which will be explored in further analysis of genetic and PRO data. Clinical trial information: NCT01824836.

Abstract Background: Two PARP inhibitors are approved for germline BRCA1/2 mutant metastatic breast cancer (MBC), based on clinical trials demonstrating an improvement in patient outcomes and quality of life. However, germline BRCA1/2 mutations are identified in 5-10% of breast cancer, limiting their potential applicability. Our prior work demonstrated that somatic BRCA1/2 mutations can be detected in cell-free DNA (cfDNA) in a proportion of patients with MBC who are not germline BRCA1/2 carriers, and that a PARP inhibitor caused growth inhibition in a circulating tumor cell line generated from a patient with MBC and a pathogenic somatic BRCA1 mutation (Vidula, Dubash, CCR, 2020). Thus, we hypothesize that a PARP inhibitor may have efficacy in somatic BRCA1/2 mutant MBC identified by cfDNA. Trial Design: This phase II investigator initiated open label clinical trial is enrolling 30 patients who have pathogenic somatic BRCA1/2 mutations found in cfDNA. Patients must not be known germline BRCA1/2 carriers. Patients receive treatment with the PARP inhibitor, talazoparib, until disease progression. Serial imaging (CT chest, abdomen, pelvis, and bone scan) occurs every 3 months, and cfDNA is collected monthly to evaluate changes in the genomic environment. Patients will also have blood collected at baseline for the Cancer Risk B assay (CR-B), a novel flow variant assay to assess double strand break repair mutations in circulating blood cells (Syeda, Genetics, 2017). Eligibility criteria: Patients with MBC (TNBC with ≥ 1 prior chemotherapy or HR+/HER2- with ≥ 1 prior hormone therapy or ineligible for hormone therapy) with a somatic BRCA1/2 mutation identified in cfDNA (established pathogenic variant) are being enrolled. Patients should not be known germline BRCA1/2 carriers (genetic testing is not required but can be obtained per physician discretion) and may not have previously received a PARP inhibitor. There is no limit on the number of prior therapies, and a prior platinum chemotherapy is allowed in the absence of disease progression on the platinum. Patients must have adequate performance status and organ function. Specific Aims: The primary endpoint is progression-free survival (PFS) using RECIST 1.1. Secondary endpoints include objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory objectives include evaluating serial changes in BRCA1/2 mutant allelic frequency in cfDNA, evaluating the impact of BRCA1/2 reversion mutations, comparing pre- and post-treatment cfDNA results to identify markers of resistance, evaluating the CR-B assay positivity rate, and ultimately correlating these analyses with treatment response. Statistical Methods: A two-stage design with 80% power to demonstrate that talazoparib is associated with “success” (PFS &gt; 12 weeks) in ≥53% patients (4% alpha) is being used. Accrual: This study (NCT03990896) is currently open at Massachusetts General Hospital, where 4 patients are completing screening for enrollment. This study will be activated soon at the University of California San Francisco, MD Anderson, Mayo Clinic Rochester and Jacksonville, Northwestern, and Emory (7 academic centers). Funding: Support for this study is provided by a Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu Citation Format: Neelima Vidula, Erica Blouch, Erin Basile, Nathan Royce Ruffle-Deignan, Nora Horick, Senthil Damodaran, Alvaro Moreno Aspitia, Manali Bhave, Ami Shah, Minetta C. Liu, Joseph Sparano, Harry Ostrer, Hope Rugo, Leif W. Ellisen, Aditya Bardia. Phase II study of a PARP inhibitor in metastatic breast cancer with somaticBRCA1/2mutations identified by cell-free DNA: Genotyping based clinical trial [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT2-24-03.

Introduction Ductal carcinoma in situ (DCIS) of the breast is a non-obligate precursor of invasive breast cancer (IBC). Many DCIS patients are either undertreated or overtreated. The overarching goal of the study described here is to facilitate detection of patients with DCIS at risk of IBC development. Here, we propose to use risk factor data and formalin-fixed paraffin-embedded (FFPE) DCIS tissue from a large, ethnically diverse, population-based cohort of 8175 women with a first diagnosis of DCIS and followed for subsequent IBC to: identify/validate miRNA expression changes in DCIS tissue associated with risk of subsequent IBC; evaluate ipsilateral IBC risk in association with two previously identified marker sets (triple immunopositivity for p16, COX-2, Ki67; Oncotype DX Breast DCIS score); examine the association of risk factor data with IBC risk. Methods and analysis We are conducting a series of case–control studies nested within the cohort. Cases are women with DCIS who developed subsequent IBC; controls (2/case) are matched to cases on calendar year of and age at DCIS diagnosis. We project 485 cases/970 controls in the aim focused on risk factors. We estimate obtaining FFPE tissue for 320 cases/640 controls for the aim focused on miRNAs; of these, 173 cases/346 controls will be included in the aim focused on p16, COX-2 and Ki67 immunopositivity, and of the latter, 156 case–control pairs will be included in the aim focused on the Oncotype DX Breast DCIS score®. Multivariate conditional logistic regression will be used for statistical analyses. Ethics and dissemination Ethics approval was obtained from the Institutional Review Boards of Albert Einstein College of Medicine (IRB 2014-3611), Kaiser Permanente Colorado, Kaiser Permanente Hawaii, Henry Ford Health System, Mayo Clinic, Marshfield Clinic Research Institute and Hackensack Meridian Health, and from Lifespan Research Protection Office. The study results will be presented at meetings and published in peer-reviewed journals.

12003 Background: AIMSS are common and frequently lead to early discontinuation of adjuvant AI therapy. Single nucleotide polymorphisms (SNPs) in candidate genes have been associated with AIMSS and AI discontinuation. The primary objective of E1Z11 was to validate previously identified associations between 10 specific SNPs in candidate genes and AI discontinuation due to AIMSS in a community-based, racially diverse cohort. Methods: Postmenopausal women with hormone receptor-positive stage I-III breast cancer enrolled onto a prospective multi-site cohort study, the majority through the NCI Community Oncology Research Program (NCORP). Participants received anastrozole 1 mg oral daily, and completed patient-reported outcomes (PROs) at baseline, 3, 6, 9, and 12 months. AIMSS was defined as >20% increase in Stanford Health Assessment Questionnaire (HAQ) score over baseline occurring within 1 year of AI therapy. We projected 40% would develop AIMSS and 25% would discontinue AI treatment within 1 year, informing a planned enrollment of 1000 women with a fixed number per strata (600 Caucasian, 200 African-American [AA] & 200 Asian) to provide 80% power to detect an effect size of 1.5-4. SNPs include ESR1 (rs2234693, rs2347868, rs9340835), CYP19A1 (rs1062033, rs4646), TCL1A (rs11849538, rs2369049, rs7158782, rs7159713), and HTR2A (rs2296972). Hardy-Weinberg equilibrium (HWE) was evaluated within each racial subset. SNP genotypes were coded as additive effects on the log odds ratio by coding as 0, 1 or 2 for the count of the minor allele. A Cochran-Armitage trend test was used with a 1-sided alpha of 0.0025 (Bonferroni correction for 10 tests). Results: We enrolled 999 evaluable women (616 Caucasian, 184 AA, 199 Asian). Genotyping was successful in 974 (98%). AIMSS developed in 43%, and AI therapy was discontinued in 12% within 1 year. While more AA and Asians developed AIMSS compared to Caucasians (48% vs 38%, p=0.017; 50% vs 38%, p=0.004), AI discontinuation rates were similar across racial groups. HWE was satisfied for all SNPs at the 5% alpha level, except for TCL1A/rs11849538 (p=0.002) in the AA cohort. None of the 10 SNPs were significantly associated with AI discontinuation or development of AIMSS in the overall population, or in any of the 3 cohorts. Conclusions: Although AIMSS were more common in AA and Asians, AI discontinuation rates were similar in the 3 cohorts. We were unable to prospectively validate 10 SNPs in 4 genes previously associated with AI discontinuation due to AIMSS. Future analyses will include other predictors of AIMSS, PROs, and additional genetic markers for the entire cohort and by race. Support: NCI UG1CA189828, UG1CA233196, UG1CA233277, UG1CA233320, UG1CA233178, UG1CA233160, UG1CA232760, UG1CA233341, UG1CA233329, U10CA180821, UG1CA189821, UG1CA189830, U10CA180888, UG1CA189859, UG1CA189863, UG1CA189971. Clinical trial information: NCT01824836.

520 Background: Systemic inflammation may contribute to cancer progression (PMC2803035), including recurrence of early breast cancer (PMC4828958). We hypothesized that inflammatory cytokines and/or chemokines may be associated with distant recurrence (DR). Methods: We performed a case:control study in women with stage II-III Her2-negative breast cancer, all of whom had surgery and adjuvant chemotherapy (doxorubicin/cyclophosphamide, then weekly paclitaxel) with/without bevacizumab, plus endocrine therapy if ER-positive (PMC6118403). Propensity score matching was used to identify approximately 250 case:control pairs (with/without DR). Serum samples obtained before adjuvant chemotherapy were analyzed using the MSD V-Plex Human Cytokine 36-Plex Kit for detection of human cytokines and chemokines involved in the Th1/Th2 pathway, chemotaxis, the Th17 pathway, angiogenesis, and immune system regulation. Conditional logistic regression analysis, with models fit via maximum likelihood, were used to estimate hazard ratios (HRs) and test for associations. Due to skewed nature of cytokines, HRs are reported on log base 2 scale. If adjusted for multiple testing including 36 markers, a p value of < 0.0014 would be required for statistical significance. Results: A total 249 matched pairs (498 patients) were identified. Covariates used for propensity score matching included age, menopausal status (post 54% vs. pre/peri 46%), ER/PR status (one/both pos 64% vs. both neg 36%) tumor size ( < = 2cm 17%, > 2-5cm 67%, > 5cm 16%) nodal status (neg 15%,1-3+ 32%, 4+ 53%), and grade (low 3%, int. 31%, high 66%). The only biomarker associated with a significantly increased DR risk when adjusted for multiple testing was the proinflammatory cytokine IL-6 (HR 1.37, 95% confidence intervals [CI] 1.15, 1.65, p = 0.0006). Others associated with a 2-sided p value < 0.05 included the chemokine MDC(macrophage-derived chemokine/CCL22) (1.90, 95% CI 1.17, 3.1, p = 0.0098), the T helper cell inflammatory cytokine IL-17A (HR 1.36, 95% CI 1.10, 1.67, p = 0.0052), and the cytokine VEGF-A (HR 1.13 for, 95% CI 1.01, 1.27, p = 0.037). There was no statistical interaction between VEGF-A and bevacizumab benefit. The median and mean value for IL-6 was 0.95 and 7.5 pg/ml (range 0.04-2761.24 pg/ml). Conclusions: This analysis provides level 1B evidence indicating that higher levels of the cytokine IL-6 at diagnosis are associated with a significantly higher DR risk in high-risk stage II-III breast cancer despite optimal adjuvant systemic therapy. This provides a foundation for confirmatory validation of IL-6 as a prognostic biomarker, and potentially as a predictive biomarker for testing therapeutic interventions targeting the IL-6/JAK/STAT3 pathway. Supported by NCI U10CA180820,180794,180821; UG1CA189859,232760,233290, 233196; Komen Foundation; Breast Cancer Research Foundation. Clinical trial information: NCT00433511.