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Macrophages Promote Circulating Tumor Cell-Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients.

ABSTRACT: Although radiotherapy (RT) decreases the incidence of locoregional recurrence in breast cancer, patients with triple-negative breast cancer (TNBC) have increased risk of local recurrence following breast-conserving therapy. The relationship between RT and local recurrence is unknown. Here, we tested the hypothesis that recurrence in some instances is due to the attraction of circulating tumor cells to irradiated tissues. To evaluate the effect of absolute lymphocyte count on local recurrence after RT in patients with TNBC, we analyzed radiation effects on tumor and immune cell recruitment to tissues in an orthotopic breast cancer model. Recurrent patients exhibited a prolonged low absolute lymphocyte count when compared with nonrecurrent patients following RT. Recruitment of tumor cells to irradiated normal tissues was enhanced in the absence of CD8+ T cells. Macrophages (CD11b+F480+) preceded tumor cell infiltration and were recruited to tissues following RT. Tumor cell recruitment was mitigated by inhibiting macrophage infiltration using maraviroc, an FDA-approved CCR5 receptor antagonist. Our work poses the intriguing possibility that excessive macrophage infiltration in the absence of lymphocytes promotes local recurrence after RT. This combination thus defines a high-risk group of patients with TNBC.Significance: This study establishes the importance of macrophages in driving tumor cell recruitment to sites of local radiation therapy and suggests that this mechanism contributes to local recurrence in women with TNBC that are also immunosuppressed.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/15/4241/F1.large.jpg Cancer Res; 78(15); 4241-52. ©2018 AACR.

SUBMITTER: Rafat M

PROVIDER: S-EPMC6072588 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Macrophages Promote Circulating Tumor Cell-Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients.

Rafat Marjan M Aguilera Todd A TA Vilalta Marta M Bronsart Laura L LL Soto Luis A LA von Eyben Rie R Golla Meghana A MA Ahrari Yasaman Y Melemenidis Stavros S Afghahi Anosheh A Jenkins Melissa J MJ Kurian Allison W AW Horst Kathleen C KC Giaccia Amato J AJ Graves Edward E EE

Cancer research 20180607 15

Although radiotherapy (RT) decreases the incidence of locoregional recurrence in breast cancer, patients with triple-negative breast cancer (TNBC) have increased risk of local recurrence following breast-conserving therapy. The relationship between RT and local recurrence is unknown. Here, we tested the hypothesis that recurrence in some instances is due to the attraction of circulating tumor cells to irradiated tissues. To evaluate the effect of absolute lymphocyte count on local recurrence aft ...[more]

PMID: 29880480

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Project description:IntroductionSalvage radiotherapy is the only curative treatment for biochemical progression after radical prostatectomy. Macroscopic recurrence may be found in the prostatic bed. The purpose of our study is to evaluate the effectiveness of salvage radiotherapy of the prostate bed with a boost to the area of the macroscopic recurrence.Material and methodsFrom January 2005 to January 2020, 89 patients with macroscopic recurrence in the prostatectomy bed were treated with salvage radiotherapy +/- hormone therapy. The average PSA level prior to radiotherapy was 1.1 ng/mL (SD: 1.6). At the time of biochemical progression, 96% of the patients had a MRI that revealed the macroscopic recurrence, and 58% had an additional choline PET scan. 67.4% of the patients got a boost to the macroscopic nodule, while 32.5% of the patients only underwent radiotherapy of the prostate bed without a boost. The median total dose of radiotherapy was 70 Gy (Min.: 60 - Max.: 74). The most commonly-used regimen was radiotherapy of the prostatectomy bed with a concomitant boost. 48% of the patients were concomitantly treated with hormone therapy.ResultsAfter a median follow-up of 53.7 months, 77 patients were alive and 12 had died, of which 4 following metastatic progression. The 5-year and 8-year survival rates (CI95%) are, respectively, 90.2% (78.9-95.6%) and 69.8% (46.4-84.4%). The 5-year biochemical progression-free survival rate (CI95%) is 50.8% (36.7-63.3). Metastatic recurrence occurred in 11.2% of the patients. We did not find any statistically significant impact from the various known prognostic factors for biochemical progression-free survival. No toxicity with a grade of > or = to 3 was found.ConclusionsOur series is one of the largest published to date. Salvage radiotherapy has its place in the management of patients with biochemical progression with local recurrence in the prostate bed, with an acceptable toxicity profile. The interest of the boost is to be evaluated in prospective trials.

Project description:Purpose: To retrospectively assess clinical outcomes and toxicity profile of prostate cancer patients treated with delayed dose-escalated image-guided salvage radiotherapy (SRT) for macroscopic local recurrence after radical prostatectomy (RP). Material and Methods: We report on a cohort of 69 consecutive patients with local recurrence after RP and no evidence of regional or distant metastasis who were referred for salvage radiotherapy between 2007 and 2016. SRT consisted of 64-66 Gy (2 Gy/fraction) to the prostatic bed followed by dose escalation to 72-74 Gy (2Gy/fraction) to the macroscopic disease. All patients received concurrent short-term androgen deprivation therapy (ADT). Biochemical recurrence-free survival (bRFS) and clinical progression-free-survival (cPFS) were depicted using Kaplan-Meier method. Multivariable Cox proportional hazards regression assessed predictors of survival outcomes. Baseline, acute, and late urinary and gastrointestinal (GI) toxicity rates were reported using CTCAE v4.03. Results: Median time from RP to SRT was 66 months (IQR: 32-124). Median pre-SRT prostate-specific antigen (PSA) was 2.7 ng/ml (IQR: 0.9-6.5). Median follow-up after SRT was 38 months (IQR: 24-66). The 3- and 5-year bRFS were 58 and 44%, respectively. The 3- and 5-year cPFS were 91 and 76%, respectively. Median time from SRT to clinical disease progression was 102 months (IQR 77.5-165). At baseline, 3 patients (4%) had grade 3 urinary symptoms. Six patients (9%) developed acute and six patients (9%) developed late grade 3 urinary toxicity. Five patients (7%) had acute grade 2 GI toxicity. No acute grade 3 GI toxicity was reported. Late grade 3 GI toxicity was reported in one patient (1.5%). Conclusions: Delayed dose-escalated SRT combined with short-course ADT for macroscopic LR after RP was associated with 44% bRFS and 76% cPFS at 5 years. Albeit improved patient stratification is warranted, these data suggest that delayed SRT provides inferior tumor control compared to early intervention.

Dataset Information

Macrophages Promote Circulating Tumor Cell-Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients.

Publications

Macrophages Promote Circulating Tumor Cell-Mediated Local Recurrence following Radiotherapy in Immunosuppressed Patients.

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