Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study

Dieci, Maria Vittoria; Criscitiello, Carmen; Goubar, Aïcha; Viale, Giuseppe; Conte, Pierfranco; Guarneri, Valentina; Ficarra, Guido; Mathieu, Marie Christine; Delaloge, Suzette; Curigliano, Giuseppe; Varga, Andrea

doi:10.1093/annonc/mdv241

Cited by 125 publications

(144 citation statements)

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“…In this dataset, CD3D, as part of immunologic signatures proven predictive of NAC response (19) and prognosis (51), was the only immunologic marker that displayed prognostic value in ER À /HER2 À patients, in the clinical multivariable model adjusting for clinical ER, PgR, and HER2, and as part of the 6-gene-predictive multivariable model. This is consistent with findings in a recent publication in which high levels of tumor-infiltrating lymphocytes, which are significantly associated with CD3D expression (19), in residual disease were associated with in improved outcome in TNBC (50). We also found a significant statistical association between IHC CD3D and mRNA expression levels, supporting the possibility of a functional association.…”

Section: /Her2supporting

confidence: 93%

“…An increase in immunologic response, represented by CD3D, CXCL13, and STAT1 has been associated with improved survival in several publications (50). In this dataset, CD3D, as part of immunologic signatures proven predictive of NAC response (19) and prognosis (51), was the only immunologic marker that displayed prognostic value in ER À /HER2 À patients, in the clinical multivariable model adjusting for clinical ER, PgR, and HER2, and as part of the 6-gene-predictive multivariable model.…”

Section: /Her2mentioning

confidence: 99%

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Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

Klintman

Buus

Cheang

et al. 2016

Clinical Cancer Research

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Purpose: The primary aim was to derive evidence for or against the clinical importance of several biologic processes in patients treated with neoadjuvant chemotherapy (NAC) by assessing expression of selected genes with prior implications in prognosis or treatment resistance. The secondary aim was to determine the prognostic impact in residual disease of the genes' expression. Experimental Design: Expression levels of 24 genes were quantified by NanoString nCounter on formalin-fixed paraffin-embedded residual tumors from 126 patients treated with NAC and 56 paired presurgical biopsies. The paired t test was used for testing changes in gene expression, and Cox regression and penalized elastic-net Cox Regression for estimating HRs. Results: After NAC, 12 genes were significantly up- and 8 downregulated. Fourteen genes were significantly associated with time to recurrence in univariable analysis in residual disease. In a multivariable model, ACACB, CD3D, MKI67, and TOP2A added prognostic value independent of clinical ER−, PgR−, and HER2− status. In ER+/HER2− patients, ACACB, PAWR, and ERBB2 predicted outcome, whereas CD3D and PAWR were prognostic in ER−/HER2− patients. By use of elastic-net analysis, a 6-gene signature (ACACB, CD3D, DECORIN, ESR1, MKI67, PLAU) was identified adding prognostic value independent of ER, PgR, and HER2. Conclusions: Most of the tested genes were significantly enriched or depleted in response to NAC. Expression levels of genes representing proliferation, stromal activation, metabolism, apoptosis, stemcellness, immunologic response, and Ras–ERK activation predicted outcome in residual disease. The multivariable gene models identified could, if validated, be used to identify patients needing additional post-neoadjuvant treatment to improve prognosis. Clin Cancer Res; 22(10); 2405–16. ©2016 AACR.

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Section: /Her2supporting

confidence: 93%

Section: /Her2mentioning

confidence: 99%

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

Klintman

Buus

Cheang

et al. 2016

Clinical Cancer Research

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“…[1][2][3][4][5][6][7] This applies to the composition of the immune infiltrate at diagnosis, [1][2][3][4]8,9 as well as for the dynamic changes induced by anthracycline-based chemotherapy, in which an amelioration of the ratio of CD8…”

Section: Introductionmentioning

confidence: 99%

The ratio of CD8⁺/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

Semeraro¹,

Adam

Stoll³

et al. 2016

OncoImmunology

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In a series of 248 tumor samples obtained from image-guided biopsies from patients diagnosed with ductal carcinoma in situ of the breast, we attempted to identify biomarkers that predict microinfiltration at definitive surgery or relapse during follow-up. For this, we used immunohistochemical methods, followed by automated image analyses, to measure the mean diameter of nuclei (which correlates with ploidy), the phosphorylation of eukaryotic initiation factor 2a (eIF2a, which reflects endoplasmic reticulum stress) as well as the density and ratio of CD8 C cytotoxic T lymphocytes and FOXP3 C regulatory T cells. The median nuclear diameter of malignant cells correlated with eIF2a phosphorylation (in cancerous tissue), which in turn correlated with the density of the CD8 C infiltrate and the CD8 C /FOXP3 ratio (both in cancerous and the adjacent non-cancerous parenchyma). Neither microinfiltration nor lymph node involvement was associated with the probability of relapse. Both correlated positively with the CD8 C /FOXP3 ratio in the malignant area. In contrast, relapse was associated with a paucity of the CD8 C infiltrate as well as an unfavorable CD8 C /FOXP3 ratio, both in malignant and non-malignant parenchyma. The combined analysis of the CD8 C /FOXP3 ratio in cancerous and non-cancerous tissues revealed a significant impact of their interaction on the probability of relapse, but not on the presence of microinfiltration or lymph node metastasis. Altogether, these results support the idea of an immunosurveillance system that determines the risk of relapse in ductal carcinoma in situ of the breast.

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“…In accordance to these studies, a meta-analysis including 16,097 patients found that rich in TILs ER− breast carcinomas were associated with favorable prognosis (33). High TILs were associated with response to neoadjuvant chemotherapy (38), in two meta-analyses including 3,251 patients (39) and 12,968 patients (40), in ER− breast carcinomas, according to a meta-analysis with 16,097 patients (33), in HER2+ breast carcinomas and TNBC (41). LPBC had a higher pCR than non-LPBC, particularly with the addition of carboplatin compared to the anthracyclin/taxane-only regimen (42).…”

Section: Hande Markers Prognostic/predictive For Disease Outcomementioning

confidence: 77%

Towards tumor immunodiagnostics

Kourea

Kotoula

2016

Ann. Transl. Med.

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Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study

Cited by 125 publications

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Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

The ratio of CD8⁺/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

Towards tumor immunodiagnostics

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Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer: a retrospective multicenter study

Cited by 125 publications

References 0 publications

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

The ratio of CD8+/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ

Towards tumor immunodiagnostics

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The ratio of CD8⁺/FOXP3 T lymphocytes infiltrating breast tissues predicts the relapse of ductal carcinoma in situ