Modifications of Immune Microenvironment Induced by Neoadjuvant Chemotherapy in Triple-negative BC

Triple Negative Breast Cancer Clinical Trial

— MIMOSA  

Official title:

Study of the Modifications of the Immune Microenvironment Induced by Neoadjuvant Chemotherapy in Triple-negative Breast Cancers

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04368468
• Other study ID #: 19HLSEIN02
• Status: Completed
• Start date: June 15, 2020
• Est. completion date: January 31, 2021

Study information

• Verified date: December 2022
• Source: Institut Claudius Regaud
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial Summary

The prescription of neoadjuvant chemotherapy becomes a standard in women with HER2-positive or triple-negative breast cancer and allows a complete histological response (pCR) which represents a prognostic factor for survival. . The problem for patients who are not pCR is that they are currently receiving non-personalized adjuvant systemic treatment.

The identification of biomarkers present in the residual disease would be a criterion to guide the choice of post-neoadjuvant adjuvant systemic treatment, in order to personalize it.

At the present time, there is no published study describing extensively the immune micro-environment (ME) in breast cancer, whether before or after chemotherapy, nor its modification induced by chemotherapy.

The team therefore propose to study in a retrospective and monocentric series, the modifications of the immune ME induced by a "standard" neo-adjuvant chemotherapy in patients with triple-negative CS, whether they are in complete histological response or not (n = twice 50).

The main objective of this project is to describe the changes in the immune ME of triple-negative breast cancers induced by neoadjuvant chemotherapy for all patients (in pCR or not):

• Quantification of TILs and subtypes of TILs (CD4 and CD8)

• Expression of the three immune checkpoints that are PDL1, TIM3 and LAG3

• Describe the organization of the immune system (immunostaining on the same slide of the PDL1, TIM3 and LAG3 immune checkpoints)

Description:

Retrospective and monocentric translational study carried out on patients treated at the IUCT-Oncopole by neoadjuvant chemotherapy (sequential treatment FEC100 or EC100 then taxane, paclitaxel weekly for the most part) for a triple-negative CS between 2012 and 2018.

We have the microbiopsy of the primary tumor preserved in FFPE and the operating room preserved in FFPE.

We have all the clinical data for the diagnosis and monitoring of these patients, already entered into a database.

The search for a BRCA germline mutation is available in most patients if indicated for an oncogenetic consultation.

biomarkers analysis :

• TILS account according to Salgado et al. before and after neoadjuvant chemotherapy

• IHC CK5-6 and EGFR then RA if the first two are negative to characterize triple negative tumors in "basal-like" and "non-basal-like"

• IHC CD3 (labeling of T lymphocytes)

• IHC CD4, CD8 and FOXP3 before and after neoadjuvant chemotherapy

• PDL1, TIM3 and LAG3 multiplex IHC before and after neoadjuvant chemotherapy

• Labeling of tumor cells: AE1 / AE3

• Use of markings for exploratory analyzes: CD68 (macrophages), CD39 (marker of lymphocyte exhaust

Recruitment information / eligibility

• Status: Completed
• Enrollment: 100
• Est. completion date: January 31, 2021
• Est. primary completion date: December 15, 2020
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Samples from triple negative BC patients, patients treated by neoadjuvant chemotherapy ( FEC or EC than taxanes) Patients consent to use their samples.

Exclusion Criteria:

• Samples not available before or after neoadjuvant chemotherapy

Related Conditions & MeSH terms

• Breast Neoplasms
• Triple Negative Breast Cancer
• Triple Negative Breast Neoplasms

Intervention

Other:
• biomarker evolution
analysis of a list of biomarkers on triple negative breast tumors samples before and after neoadjuvant therapy

Locations

Country	Name	City	State
France	Institut claudius regaud	Toulouse

Sponsors (1)

Lead Sponsor	Collaborator
Institut Claudius Regaud

Country where clinical trial is conducted

France, 

References & Publications (25)

Adams S, Gray RJ, Demaria S, Goldstein L, Perez EA, Shulman LN, Martino S, Wang M, Jones VE, Saphner TJ, Wolff AC, Wood WC, Davidson NE, Sledge GW, Sparano JA, Badve SS. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers — View Citation

Bates GJ, Fox SB, Han C, Leek RD, Garcia JF, Harris AL, Banham AH. Quantification of regulatory T cells enables the identification of high-risk breast cancer patients and those at risk of late relapse. J Clin Oncol. 2006 Dec 1;24(34):5373-80. doi: 10.1200 — View Citation

Burugu S, Gao D, Leung S, Chia SK, Nielsen TO. LAG-3+ tumor infiltrating lymphocytes in breast cancer: clinical correlates and association with PD-1/PD-L1+ tumors. Ann Oncol. 2017 Dec 1;28(12):2977-2984. doi: 10.1093/annonc/mdx557. — View Citation

Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, Bonnefoi H, Cameron D, Gianni L, Valagussa P, Swain SM, Prowell T, Loibl S, Wickerham DL, Bogaerts J, Baselga J, Perou C, Blumenthal G, Blohmer J, Mamounas EP, Bergh J, Semiglazov V, Justice — View Citation

DeNardo DG, Barreto JB, Andreu P, Vasquez L, Tawfik D, Kolhatkar N, Coussens LM. CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. Cancer Cell. 2009 Aug 4;16(2):91-102. doi: 10.1016/j.ccr.2 — View Citation

Denkert C, Loibl S, Noske A, Roller M, Muller BM, Komor M, Budczies J, Darb-Esfahani S, Kronenwett R, Hanusch C, von Torne C, Weichert W, Engels K, Solbach C, Schrader I, Dietel M, von Minckwitz G. Tumor-associated lymphocytes as an independent predictor — View Citation

Denkert C, von Minckwitz G, Brase JC, Sinn BV, Gade S, Kronenwett R, Pfitzner BM, Salat C, Loi S, Schmitt WD, Schem C, Fisch K, Darb-Esfahani S, Mehta K, Sotiriou C, Wienert S, Klare P, Andre F, Klauschen F, Blohmer JU, Krappmann K, Schmidt M, Tesch H, Ku — View Citation

Dieci MV, Criscitiello C, Goubar A, Viale G, Conte P, Guarneri V, Ficarra G, Mathieu MC, Delaloge S, Curigliano G, Andre F. Prognostic value of tumor-infiltrating lymphocytes on residual disease after primary chemotherapy for triple-negative breast cancer — View Citation

Gu-Trantien C, Loi S, Garaud S, Equeter C, Libin M, de Wind A, Ravoet M, Le Buanec H, Sibille C, Manfouo-Foutsop G, Veys I, Haibe-Kains B, Singhal SK, Michiels S, Rothe F, Salgado R, Duvillier H, Ignatiadis M, Desmedt C, Bron D, Larsimont D, Piccart M, So — View Citation

Ladoire S, Mignot G, Dabakuyo S, Arnould L, Apetoh L, Rebe C, Coudert B, Martin F, Bizollon MH, Vanoli A, Coutant C, Fumoleau P, Bonnetain F, Ghiringhelli F. In situ immune response after neoadjuvant chemotherapy for breast cancer predicts survival. J Pat — View Citation

Loi S, Drubay D, Adams S, Pruneri G, Francis PA, Lacroix-Triki M, Joensuu H, Dieci MV, Badve S, Demaria S, Gray R, Munzone E, Lemonnier J, Sotiriou C, Piccart MJ, Kellokumpu-Lehtinen PL, Vingiani A, Gray K, Andre F, Denkert C, Salgado R, Michiels S. Tumor — View Citation

Loi S, Dushyanthen S, Beavis PA, Salgado R, Denkert C, Savas P, Combs S, Rimm DL, Giltnane JM, Estrada MV, Sanchez V, Sanders ME, Cook RS, Pilkinton MA, Mallal SA, Wang K, Miller VA, Stephens PJ, Yelensky R, Doimi FD, Gomez H, Ryzhov SV, Darcy PK, Arteaga — View Citation

Loi S, Sirtaine N, Piette F, Salgado R, Viale G, Van Eenoo F, Rouas G, Francis P, Crown JP, Hitre E, de Azambuja E, Quinaux E, Di Leo A, Michiels S, Piccart MJ, Sotiriou C. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III r — View Citation

Mahmoud SM, Lee AH, Paish EC, Macmillan RD, Ellis IO, Green AR. The prognostic significance of B lymphocytes in invasive carcinoma of the breast. Breast Cancer Res Treat. 2012 Apr;132(2):545-53. doi: 10.1007/s10549-011-1620-1. Epub 2011 Jun 14. — View Citation

Mahmoud SM, Lee AH, Paish EC, Macmillan RD, Ellis IO, Green AR. Tumour-infiltrating macrophages and clinical outcome in breast cancer. J Clin Pathol. 2012 Feb;65(2):159-63. doi: 10.1136/jclinpath-2011-200355. Epub 2011 Nov 2. — View Citation

Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Grainge MJ, Lee AH, Ellis IO, Green AR. Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011 May 20;29(15):1949-55. doi: 10.1200/JCO.2010.30.5037. Epub 2011 Apr 11. — View Citation

Mahmoud SM, Paish EC, Powe DG, Macmillan RD, Lee AH, Ellis IO, Green AR. An evaluation of the clinical significance of FOXP3+ infiltrating cells in human breast cancer. Breast Cancer Res Treat. 2011 May;127(1):99-108. doi: 10.1007/s10549-010-0987-8. Epub — View Citation

Mamessier E, Sylvain A, Thibult ML, Houvenaeghel G, Jacquemier J, Castellano R, Goncalves A, Andre P, Romagne F, Thibault G, Viens P, Birnbaum D, Bertucci F, Moretta A, Olive D. Human breast cancer cells enhance self tolerance by promoting evasion from NK — View Citation

Masuda N, Lee SJ, Ohtani S, Im YH, Lee ES, Yokota I, Kuroi K, Im SA, Park BW, Kim SB, Yanagita Y, Ohno S, Takao S, Aogi K, Iwata H, Jeong J, Kim A, Park KH, Sasano H, Ohashi Y, Toi M. Adjuvant Capecitabine for Breast Cancer after Preoperative Chemotherapy — View Citation

Miyashita M, Sasano H, Tamaki K, Hirakawa H, Takahashi Y, Nakagawa S, Watanabe G, Tada H, Suzuki A, Ohuchi N, Ishida T. Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after — View Citation

Pusztai L, Foldi J, Dhawan A, DiGiovanna MP, Mamounas EP. Changing frameworks in treatment sequencing of triple-negative and HER2-positive, early-stage breast cancers. Lancet Oncol. 2019 Jul;20(7):e390-e396. doi: 10.1016/S1470-2045(19)30158-5. — View Citation

Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, Wienert S, Van den Eynden G, Baehner FL, Penault-Llorca F, Perez EA, Thompson EA, Symmans WF, Richardson AL, Brock J, Criscitiello C, Bailey H, Ignatiadis M, Floris G, Sparano J, Kos Z, — View Citation

Symmans WF, Peintinger F, Hatzis C, Rajan R, Kuerer H, Valero V, Assad L, Poniecka A, Hennessy B, Green M, Buzdar AU, Singletary SE, Hortobagyi GN, Pusztai L. Measurement of residual breast cancer burden to predict survival after neoadjuvant chemotherapy. — View Citation

Thibaudin M, Chaix M, Boidot R, Vegran F, Derangere V, Limagne E, Berger H, Ladoire S, Apetoh L, Ghiringhelli F. Human ectonucleotidase-expressing CD25high Th17 cells accumulate in breast cancer tumors and exert immunosuppressive functions. Oncoimmunology — View Citation

von Minckwitz G, Huang CS, Mano MS, Loibl S, Mamounas EP, Untch M, Wolmark N, Rastogi P, Schneeweiss A, Redondo A, Fischer HH, Jacot W, Conlin AK, Arce-Salinas C, Wapnir IL, Jackisch C, DiGiovanna MP, Fasching PA, Crown JP, Wulfing P, Shao Z, Rota Caremol — View Citation

* Note: There are 25 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Identify Change of immune ME by TILS quantification of triple-negative breast cancer induced by neoadjuvant chemotherapy for all patients	TILS ans substype quantification	12 months
Primary	Identify Change of immune ME by PDL1 expression of triple-negative breast cancer induced by neoadjuvant chemotherapy for all patients	expression of PDL1,	12 months
Primary	Identify Change of immune ME by TIM3 expression of triple-negative breast cancer induced by neoadjuvant chemotherapy for all patients	expression of TIM3	12 months
Primary	Identify Change of immune ME by LAG3 expression of triple-negative breast cancer induced by neoadjuvant chemotherapy for all patients	LAG3 expression	12 months
Secondary	Compare change ofTILs quantification of triple-negative breast cancer induced by neoadjuvant chemotherapy for pCR patients and those not pCR and for subtype basal-like or not basal-like	Quantification of TILs and subtypes TILs;	12 months
Secondary	Compare change of PDL1 expression of triple-negative breast cancer induced by neoadjuvant chemotherapy for pCR patients and those not pCR and for subtype basal-like or not basal-like	expression of PDL1	12 months
Secondary	Compare change of TIM3 expression of triple-negative breast cancer induced by neoadjuvant chemotherapy for pCR patients and those not pCR and for subtype basal-like or not basal-like	expression of TIM3	12 months
Secondary	Compare change of LAG3 expression of triple-negative breast cancer induced by neoadjuvant chemotherapy for pCR patients and those not pCR and for subtype basal-like or not basal-like	expression of LAG3; organization of immune system	12 months
Secondary	determination of predictive factors of TILs quantification for response to neoadjuvant chemotherapy and disease free survival	Correlation between TILs and TILs substypes quantification (on microbiopsy) and the histological response after neoadjuvant chemotherapy (pCR versus non pCR): determination of predictive factors for response to chemotherapy.	12 months
Secondary	determination of predictive factors of PDL1 expression for response to neoadjuvant chemotherapy and disease free survival	Correlation between PDL1 expression on microbiopsy and the histological response after neoadjuvant chemotherapy (pCR versus non pCR): determination of predictive factors for response to chemotherapy.	12 months
Secondary	determination of predictive factors of TIM3 for response to neoadjuvant chemotherapy and disease free survival	Correlation between TIM3 expression on microbiopsy and the histological response after neoadjuvant chemotherapy (pCR versus non pCR): determination of predictive factors for response to chemotherapy.	12 months
Secondary	determination of predictive factors of LAG3 for response to neoadjuvant chemotherapy and disease free survival	Correlation between LAG3 expression on microbiopsy and the histological response after neoadjuvant chemotherapy (pCR versus non pCR): determination of predictive factors for response to chemotherapy.	12 months