In early stage breast cancer, the degree of tumor-infiltrating lymphocytes (TILs) predicts response to chemotherapy and overall survival. Combination immunotherapy with immune checkpoint antibody plus tumor cryoablation can induce lymphocytic infiltrates and improve survival in mice. We used T-cell receptor (TCR) DNA sequencing to evaluate both the effect of cryoimmunotherapy in humans and the feasibility of TCR sequencing in early-stage breast cancer. In a pilot clinical trial, 18 women with early-stage breast cancer were treated preoperatively with cryoablation, single-dose anti-CTLA-4 (ipilimumab), or cryoablation + ipilimumab. TCRs within serially collected peripheral blood and tumor tissue were sequenced. In baseline tumor tissues, Tcell density as measured by TCR sequencing correlated with TIL scores obtained by hematoxylin and eosin (H&E) staining. However, tumors with little or no lymphocytes by H&E contained up to 3.6 × 10 6 TCR DNA sequences, highlighting the sensitivity of the ImmunoSEQ platform. In this dataset, ipilimumab increased intratumoral T-cell density over time, whereas cryoablation ± ipilimumab diversified and remodeled the intratumoral T-cell clonal repertoire. Compared to
#4104 Background: Dose dense (dd) q2wk AC-paclitaxel (P) is superior to q3wk AC-P. Both regimens are associated with a <1% incidence of CHF. In MBC, q3wk nanoparticle albumin-bound paclitaxel (nab-P) is superior to q3wk P and bevacizumab (B) improves progression-free survival when added to P. Based on the MBC data, B may be more effective when targeting minimal residual disease in the adjuvant setting and nab-P may offer superior efficacy with reduced toxicity. However, it is uncertain whether AC plus B increases the risk of CHF. We evaluated the cardiac safety of ddAC-nab-P with concurrent B as adjuvant therapy for BC.
 Methods: Based upon the accepted cardiac event (CE) rate of approximately 4% in trials with adjuvant trastuzumab, this study was designed with similar monitoring and tolerability thresholds. The primary endpoint is cardiac safety: symptomatic CHF or death from LV dysfunction. Secondary endpoints are toxicity, DFS, OS, and biomarkers for efficacy and toxicity. Eligible pts have resected HER2(-) BC and normal LVEF. B is administered concurrently (10 mg/kg IV q2wk x 8) with chemotherapy (AC at 60/600 mg/m2 q2wk x 4 then nab-P at 260 mg/m2 q2wk x 4) and continues at 15 mg/kg q3wk thereafter for a total one year of B therapy. Pegfilgrastim is administered Day 2 of each chemotherapy cycle. Radiation and endocrine therapy are administered per standard of care. MUGAs are obtained at baseline and mos 2, 6, 9 and 18. Although asymptomatic LVEF declines are not considered CEs, B may be held per protocol and long-term cardiac monitoring initiated. If 3 CEs or > 1 cardiac death from LV dysfunction occur, B + ddAC-nab-P will not be considered safe.
 Results: The target accrual of 80 pts has been met. Median age is 47y (27-75). As of May 31, 2008, median follow-up is 14 mo (1-21) and 51 pts have completed 1y of planned therapy. No patients have developed symptomatic LV dysfunction at any point during study therapy. Sixteen pts have discontinued treatment due to toxicity: asymptomatic LVEF decline (N=3), hypertension (N=3), wound healing (N=3), headache (N=2), sensory neuropathy (N=2), pain (N=1), hypersensitivity reaction (N=1), and pneumonitis (N=1). Three pts had disease progression, and 8 pts withdrew consent.
 
 Conclusions: At the time of this analysis, no symptomatic LV dysfunction has been observed with B + ddAC-nab-P. Follow-up is ongoing. Correlative studies, including analysis of troponin, renin, and circulating endothelial and tumor cells, are underway. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 4104.
Introduction: For women with high risk early breast cancer that overexpresses HER2, the role of adjuvant T with chemotherapy is well established. Although the benefits of this approach in women with small, node negative tumors are less well defined, we previously published a retrospective sequential cohort study that suggested that T with chemotherapy is active in this setting. However there are few data about the safety and efficacy of adjuvant T in older women with small, node negative HER2+ breast cancer. Thus, this we conducted a retrospective study of breast cancer specific and cardiac outcomes for this subset. Methods: From our previously reported dataset, we identified women > 60y with <2 cm, node-negative HER2+ breast cancer. We identified a “no-T” cohort of 32 women diagnosed Jan ‘02 - May ‘05 and a “T” cohort of 39 patients diagnosed May ‘05 - Dec ‘08. Electronic medical records were reviewed to examine risk factors and incidence of cardiotoxicity as well as patient outcomes including distant disease-free survival (DDFS) and overall survival (OS). Results: Women in the two cohorts had similar baseline characteristics including cardiac risk factors (Table 1). There were no cardiac events in the no-T group. In the T group, 3 patients discontinued T due to a cardiac event: 1 with asymptomatic decline in ejection fraction (EF), 1 with atrial fibrillation and dyspnea, and 1 with symptomatic EF decline associated with myocardial infarct and valvular disease. Patients in both cohorts had excellent disease control at a median follow up of 9y and 6y for the no-T and T cohorts respectively. The 3y DDFS numerically favors the T cohort, the confidence intervals are broad and overlapping (Table 1). There were no detectable differences in OS between groups. In our previous report (not selected for age), DDFS at 3yrs was 95% (90-99) and 100% in the no-T (N = 106) and T (N = 155) cohorts respectively. Conclusion: In this small retrospective study, older women with small, node negative HER2+ breast cancers had excellent disease control and a low risk of cardiotoxicity. The possible benefits of T in this setting are consistent with prior reports uncontrolled for age. Table 1 No Trastuzumab N = 32 N (%)Trastuzumab N = 39 N (%)Tumor Size (cm), median (range)1.4 (0.1-2.0)1.3 (0.5-2.0)Multifocal Disease6 (19)4 (10)Grade 324 (75)33 (85)ER Positive20 (63)20 (51)Age, median (range)66 (60-85)65 (60-82)BMI, median (range)24.7 (18.2-34.2)27.3 (18.2-47.1)Chemotherapy16 (50)39 (100)Radiotherapy23 (72)25 (64)Hypercholesterolemia11 (34)18 (46)Hypertension12 (38)13 (33)3yr DDFS (95% CI)91% (74-97)97% (83-100)3yr OS (95% CI)97% (80-100)97% (83-100) Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-11.
Background: In mTNBC, anti-PD-1/L1 monotherapy is most effective when administered early in the course of disease, with recent trials demonstrating overall response rates (ORR) of 23-26% in the first-line setting and 5-6% in later lines. This may reflect iatrogenic lymphopenia from preceding cytotoxic chemotherapy. Furthermore, curative-intent chemotherapy is associated with prolonged suppression of naïve CD4+ cells, a T-cell subset that may play a critical role in the generation of de novo anti-tumor immune responses. We present the final clinical results of a pilot study evaluating the safety and efficacy of combining pembrolizumab plus standard-of-care capecitabine in the first/second-line mTNBC setting. We also explore potential associations between clinical benefit and lymphopenia, preceding chemotherapy, and absolute naïve CD4+ counts. Methods: In a pilot study, we evaluated the tolerability and preliminary efficacy of concurrent pembro (200mg IV q21 day) plus investigator-selected 1st/2nd line paclitaxel (80mg/m2 IV weekly) or oral cape (2,000mg BID, weekly 1 on/1 off). The primary endpoint was tolerability, defined as the proportion of subjects receiving >6 weeks concurrent therapy without dose discontinuation with toxicities reported per CTCAE v4.0. The secondary endpoint was 12-week objective response rate (ORR) by RECIST1.1. Exploratory endpoints included peripheral blood cell enumeration by real-time flow cytometry and routine clinical laboratory. Naïve CD4+ cells were defined as CD45+ CD3+ TCRab+ CD4+ CD45RA+ CCR7+. Here, we report the results of the pilot phase of the cape cohort (NCT02734290). Results: Twelve of 14 subjects were treated in the first-line setting. All subjects (14/14, 100%) tolerated cape+pembro for >6 weeks, with toxicities consistent with monotherapy cape experience (diarrhea: grade I-II 50%, grade III 7%; hand-foot: grade I-II 71%) that improved with dose-reduction as needed. At 12 weeks, the ORR was 6/14 (42.9%), and the clinical benefit rate (ORR + stable disease) was 8/14 (57.1%). Depressed absolute lymphocyte count at baseline (ALC<1.0/uL: 33% CBR; ALC≥1.0/uL: 75% CBR) and recent exposure to cytotoxic chemotherapy (<6 months: 33% CBR; >6 months: 75% CBR) were associated with reduced clinical benefit. By flow cytometry, subjects experiencing clinical benefit had higher baseline absolute naïve CD4+ counts (average 283 cells/uL v. 93 cells/uL, p=.069). Conclusions: This study met the primary endpoint of safety for cape plus pembro in mTNBC, with encouraging clinical activity. These data are supportive of further studies evaluating combination chemotherapy plus anti-PD-1/L1 mTNBC. We observed greater clinical benefit in subjects with non-suppressed ALC, less exposure to recent chemo, and higher baseline naïve CD4+ counts, suggesting that iatrogenic immunosuppression can impair response to immune checkpoint therapy in mTNBC. These findings should be confirmed in ongoing randomized trials of immune checkpoint +/- chemotherapy in mTNBC, and should be considered in the design of future clinical trials. Citation Format: Page DB, Pucilowska J, Bennetts L, Kim I, Sanchez K, Martel M, Conlin A, Moxon N, Mellinger S, Acheson A, Kemmer K, Mitri Z, Vuky J, Ahn J, Abaya C, Manigault T, Basho R, Urba WJ, McArthur HL. Updated efficacy of first or second-line pembrolizumab (pembro) plus capecitabine (cape) in metastatic triple negative breast cancer (mTNBC) and correlations with baseline lymphocyte and naïve CD4+ T-cell count [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 P2-09-03.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.