Immune profiling of pre- and post-treatment breast cancer tissues from the SWOG S0800 neoadjuvant trial

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Abstract

Background

How the immune microenvironment changes during neoadjuvant chemotherapy of primary breast cancer is not well understood.

Methods

We analyzed pre- and post-treatment samples from 60 patients using the NanoString PanCancer IO360™ assay to measure the expression of 750 immune-related genes corresponding to 14 immune cell types and various immune functions, and assessed TIL counts and PD-L1 protein expression by immunohistochemistry. Treatment associated changes in gene expression levels were compared using t-test with Bonferroni correction. TIL count, PD-L1 protein and immune metagenes were compared using Wilcoxon test. Baseline immune markers were correlated with pathologic complete response (pCR) using estrogen receptor and treatment arm adjusted logistic regression.

Results

At baseline, high TIL counts and high expression of chemoattractant cytokines (CCL21, CCL19) and cytotoxic T cell markers were associated with higher pCR rate. High expression of stromal genes (VEGFB, TGFB3, PDGFB, FGFR1, IGFR1), mast and myeloid inflammatory cell metagenes, stem cell related genes (CD90, WNT11, CTNNB1) and CX3CR1, and IL11RA were associated with residual disease (RD). After treatment, in cases with pCR, TIL counts and most immune genes decreased significantly. Among RD cases, TIL counts and PD-L1 expression did not change but cellular stress and hypoxia associated genes (DUSP1, EGR1), and IL6, CD36, CXCL2, CD69 and the IL8/VEGF metagene increased.

Conclusions

Activated T cells in the tumor microenvironment are associated with pCR whereas stromal functions are associated with residual disease. Most immune functions decrease during neoadjuvant chemotherapy but several immunotherapy targets (PD-L1, IL6, IL8) remain expressed in RD suggesting potential therapeutic strategies.

Electronic supplementary material

The online version of this article (10.1186/s40425-019-0563-7) contains supplementary material, which is available to authorized users.

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Most cited references 11

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Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer.

Carsten Denkert, Sibylle Loibl, Aurelia Noske … (2010)

PURPOSE Preclinical data suggest a contribution of the immune system to chemotherapy response. In this study, we investigated the prespecified hypothesis that the presence of a lymphocytic infiltrate in cancer tissue predicts the response to neoadjuvant chemotherapy. METHODS We investigated intratumoral and stromal lymphocytes in a total of 1,058 pretherapeutic breast cancer core biopsies from two neoadjuvant anthracycline/taxane-based studies (GeparDuo, n = 218, training cohort; and GeparTrio, n = 840, validation cohort). Molecular parameters of lymphocyte recruitment and activation were evaluated by kinetic polymerase chain reaction in 134 formalin-fixed, paraffin-embedded tumor samples. Results In a multivariate regression analysis including all known predictive clinicopathologic factors, the percentage of intratumoral lymphocytes was a significant independent parameter for pathologic complete response (pCR) in both cohorts (training cohort: P = .012; validation cohort: P = .001). Lymphocyte-predominant breast cancer responded, with pCR rates of 42% (training cohort) and 40% (validation cohort). In contrast, those tumors without any infiltrating lymphocytes had pCR rates of 3% (training cohort) and 7% (validation cohort). The expression of inflammatory marker genes and proteins was linked to the histopathologic infiltrate, and logistic regression showed a significant association of the T-cell-related markers CD3D and CXCL9 with pCR. CONCLUSION The presence of tumor-associated lymphocytes in breast cancer is a new independent predictor of response to anthracycline/taxane neoadjuvant chemotherapy and provides useful information for oncologists to identify a subgroup of patients with a high benefit from this type of chemotherapy.

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Immune parameters affecting the efficacy of chemotherapeutic regimens.

Laurence Zitvogel, Oliver Kepp, Guido Kroemer (2011)

The outcome of chemotherapy can be influenced by the host immune system at multiple levels. Chemotherapy can kill cancer cells by causing them to elicit an immune response or alternatively, by increasing their susceptibility to immune attack. In addition, chemotherapy can stimulate anticancer immune effectors either in a direct fashion or by subverting immunosuppressive mechanisms. Beyond cancer-cell-intrinsic factors that determine the cytotoxic or cytostatic response, as well as the potential immunogenicity of tumor cells, the functional state of the host immune system has a major prognostic and predictive impact on the fate of cancer patients treated with conventional or targeted chemotherapies. In this Review, we surmise that immune-relevant biomarkers may guide personalized therapeutic interventions including compensatory measures to restore or improve anticancer immune responses.

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Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype

W Symmans, Caimiao Wei, Rebekah E Gould … (2017)

Purpose To determine the long-term prognosis in each phenotypic subset of breast cancer related to residual cancer burden (RCB) after neoadjuvant chemotherapy alone, or with concurrent human epidermal growth factor receptor 2 (HER2)–targeted treatment. Methods We conducted a pathologic review to measure the continuous RCB index (wherein pathologic complete response has RCB = 0; residual disease is categorized into three predefined classes of RCB index [RCB-I, RCB-II, and RCB-III]), and yp-stage of residual disease. Patients were prospectively observed for survival. Three patient cohorts received paclitaxel (T) followed by fluorouracil, doxorubicin, and cyclophosphamide (T/FAC): original development cohort (T/FAC-1), validation cohort (T/FAC-2), and independent validation cohort (T/FAC-3). Another validation cohort received FAC chemotherapy only, and a fifth cohort received concurrent trastuzumab (H) with sequential paclitaxel and fluorouracil, epirubicin, and cyclophosphamide (FEC; H+T/FEC). Phenotypic subsets were defined by hormone receptor (HR) and HER2 status at diagnosis, classified as HR-positive/HER2-negative, HER2-positive (HR-negative/HER2-positive or HR-positive/HER2-positive), or triple receptor–negative. Relapse-free survival estimates were determined from Kaplan-Meier analysis and compared using the log-rank test. Results Five cohorts (T/FAC-1 [n = 219], T/FAC-2 [n = 262], T/FAC-3 [n = 342], FAC [n = 132], and H+T/FEC [n = 203]) had median event-free follow-up of 13.5, 9.1, 6.8, 16.4, and 7.1 years, respectively. Continuous RCB index was prognostic within each phenotypic subset, independent of other clinical-pathologic variables. RCB classes stratified prognostic risk overall, within each phenotypic subset, and within yp-stage categories. Estimates of 10-year relapse-free survival rates in the four RCB classes (pathologic complete response, RCB-I, RCB-II, and RCB-III) were 86%, 81%, 55%, and 23% for triple receptor–negative; 83%, 97%, 74%, and 52% for HR-positive/HER2-negative in the combined T/FAC cohorts; and 95%, 77%, 47%, and 21% in the H+T/FEC cohort. Conclusion RCB was prognostic for long-term survival after neoadjuvant chemotherapy in all three phenotypic subsets of breast cancer. Our institutional findings should be externally validated.

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Author and article information

Contributors

Xiaotong Li: xiaotong.li@yale.edu

Sarah Warren: swarren@nanostring.com

Vasiliki Pelekanou: vasiliki.pelekanou@gmail.com

Vikram Wali: vikram.wali@yale.edu

Alessandra Cesano: acesano@nanostring.com

Mingdong Liu: miliu@nanostring.com

Patrick Danaher: patrickjdanaher@gmail.com

Nathane Elliott: nelliott@nanostring.com

Zeina A. Nahleh: nahlehz@ccf.org

Daniel F. Hayes: hayesdf@med.umich.edu

Gabriel N. Hortobagyi: ghortoba@mdanderson.org

William E. Barlow: williamb@crab.org

Christos Hatzis: christos.hatzis@yale.edu

Lajos Pusztai: +1 203 737 6858 , lajos.pusztai@yale.edu

Journal

Journal ID (nlm-ta): J Immunother Cancer

Journal ID (iso-abbrev): J Immunother Cancer

Title: Journal for Immunotherapy of Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 2051-1426

Publication date (Electronic): 10 April 2019

Publication date PMC-release: 10 April 2019

Publication date Collection: 2019

Volume: 7

Electronic Location Identifier: 88

Affiliations

[1 ]ISNI 0000000419368710, GRID grid.47100.32, Yale Cancer Center, Breast Medical Oncology, , Yale School of Medicine, ; 300 George Street, Suite 120, Rm133, New Haven, CT 06511 USA

[2 ]NanoString Technologies Inc., Seattle, WA USA

[3 ]ISNI 0000000419368710, GRID grid.47100.32, Department of Pathology, , Yale School of Medicine, ; New Haven, CT USA

[4 ]ISNI 0000 0004 0481 997X, GRID grid.418628.1, Cleveland Clinic Florida, Maroone Cancer Center, ; Weston, FL USA

[5 ]ISNI 0000000086837370, GRID grid.214458.e, University of Michigan Rogel Cancer Center, ; Ann Arbor, MI USA

[6 ]ISNI 0000 0001 2291 4776, GRID grid.240145.6, University of Texas MD Anderson Cancer Center, ; Houston, TX USA

[7 ]SWOG Statistical Center, Seattle, WA USA

Article

Publisher ID: 563

DOI: 10.1186/s40425-019-0563-7

PMC ID: 6457012

PubMed ID: 30967156

SO-VID: 502da06a-9aef-4b4f-8e88-9eba361a73c6

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 12 October 2018

Date accepted : 12 March 2019

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000009, Foundation for the National Institutes of Health;

Award ID: CA180888, CA180819, CA180826, CA180801, CA180858

Award Recipient : Lajos Pusztai

Funded by: Breast Cancer Research Foundation

Award ID: NA

Award Recipient : Daniel F. Hayes Christos Hatzis Lajos Pusztai

Funded by: FundRef http://dx.doi.org/10.13039/100009634, Susan G. Komen;

Award ID: NA

Award Recipient : Lajos Pusztai

Custom metadata

Keywords: tumor infiltrating lymphocytes,pd-l1,immune-related genes,neoadjuvant treatment,bevacizumab

Data availability:

Keywords: tumor infiltrating lymphocytes, pd-l1, immune-related genes, neoadjuvant treatment, bevacizumab

Immune profiling of pre- and post-treatment breast cancer tissues from the SWOG S0800 neoadjuvant trial

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Abstract

Background

Methods

Results

Conclusions

Electronic supplementary material

Related collections

HLA-G and immune tolerance in pregnancy

Most cited references 11

Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer.

Immune parameters affecting the efficacy of chemotherapeutic regimens.

Long-Term Prognostic Risk After Neoadjuvant Chemotherapy Associated With Residual Cancer Burden and Breast Cancer Subtype

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