Skip to main content
Erschienen in: Annals of Surgical Oncology 4/2018

12.01.2018 | Breast Oncology

Prognostic Value of Tumor-Infiltrating Lymphocyte Density Assessed Using a Standardized Method Based on Molecular Subtypes and Adjuvant Chemotherapy in Invasive Breast Cancer

verfasst von: Nuri Jang, MD, Hee Jung Kwon, MD, Min Hui Park, BS, Su Hwan Kang, MD, Young Kyung Bae, MD, PhD

Erschienen in: Annals of Surgical Oncology | Ausgabe 4/2018

Einloggen, um Zugang zu erhalten

Abstract

Background

This study investigated the prognostic value of tumor-infiltrating lymphocyte (TIL) density as determined by molecular subtype and receipt of adjuvant chemotherapy in invasive breast cancer (IBC).

Methods

Stromal TIL densities were evaluated in 1489 IBC samples using recommendations proposed by the International TILs Working Group. Cases were allocated to high- and low-TIL density groups using a cutoff of 10%.

Results

Of the 1489 IBC patients, 427 (28.7%) were assigned to the high-TIL group and 1062 (71.3%) to the low-TIL group. High TIL density was found to be significantly associated with large tumor size (p = 0.001), high histologic grade (p < 0.001), and high Ki-67 labeling index (p < 0.001). Triple-negative and human epidermal growth factor receptor 2 (HER2)-positive subtypes had significantly higher TIL densities than luminal A or B (HER2-negative) subtypes (p < 0.001). High TIL density was significantly associated with prolonged disease-free survival (DFS) by univariate (p < 0.001) and multivariate (p < 0.001) analyses. In the low-TIL-density group, the patients who did not receive adjuvant chemotherapy showed better DFS (p < 0.001), but no such survival difference was observed in the high-TIL group (p = 0.222). For the patients who received adjuvant anthracycline, high-TIL density was found to be an independent prognostic factor of favorable DFS in the luminal B (HER2-negative; p = 0.003), HER2-positive (p = 0.019), and triple-negative (p = 0.017) subtypes.

Conclusion

Measurements of TIL density in routine clinical practice could give useful prognostic information for the triple-negative, HER2-positive, and luminal B (HER2-negative) IBC subtypes, especially for patients administered adjuvant anthracycline.
Anhänge
Nur mit Berechtigung zugänglich
Literatur
1.
Zurück zum Zitat Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28:105–13.CrossRefPubMed Denkert C, Loibl S, Noske A, et al. Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. J Clin Oncol. 2010;28:105–13.CrossRefPubMed
2.
Zurück zum Zitat Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31:860–7.CrossRefPubMed Loi S, Sirtaine N, Piette F, et al. Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol. 2013;31:860–7.CrossRefPubMed
3.
Zurück zum Zitat Seo AN, Lee HJ, Kim EJ, et al. Tumour-infiltrating CD8 + lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br J Cancer. 2013;109:2705–13.CrossRefPubMedPubMedCentral Seo AN, Lee HJ, Kim EJ, et al. Tumour-infiltrating CD8 + lymphocytes as an independent predictive factor for pathological complete response to primary systemic therapy in breast cancer. Br J Cancer. 2013;109:2705–13.CrossRefPubMedPubMedCentral
4.
Zurück zum Zitat Adams S, Gray RJ, Demaria S, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014;32:2959–66.CrossRefPubMedPubMedCentral Adams S, Gray RJ, Demaria S, et al. Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. J Clin Oncol. 2014;32:2959–66.CrossRefPubMedPubMedCentral
5.
Zurück zum Zitat Loi S, Michiels S, Salgado R, et al. Tumor-infiltrating lymphocytes are prognostic in triple-negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25:1544–50.CrossRefPubMed Loi S, Michiels S, Salgado R, et al. Tumor-infiltrating lymphocytes are prognostic in triple-negative breast cancer and predictive for trastuzumab benefit in early breast cancer: results from the FinHER trial. Ann Oncol. 2014;25:1544–50.CrossRefPubMed
6.
Zurück zum Zitat Mao Y, Qu Q, Zhang Y, Liu J, Chen X, Shen K. The value of tumor infiltrating lymphocytes (TILs) for predicting response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. PLoS One. 2014;9:e115103.CrossRefPubMedPubMedCentral Mao Y, Qu Q, Zhang Y, Liu J, Chen X, Shen K. The value of tumor infiltrating lymphocytes (TILs) for predicting response to neoadjuvant chemotherapy in breast cancer: a systematic review and meta-analysis. PLoS One. 2014;9:e115103.CrossRefPubMedPubMedCentral
7.
Zurück zum Zitat Denkert C, von Minckwitz G, Brase JC, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015;33:983–91.CrossRefPubMed Denkert C, von Minckwitz G, Brase JC, et al. Tumor-infiltrating lymphocytes and response to neoadjuvant chemotherapy with or without carboplatin in human epidermal growth factor receptor 2-positive and triple-negative primary breast cancers. J Clin Oncol. 2015;33:983–91.CrossRefPubMed
8.
Zurück zum Zitat Gnant M, Harbeck N, Thomssen C. St. Gallen/Vienna 2017: a brief summary of the consensus discussion about escalation and de-escalation of primary breast cancer treatment. Breast Care Basel. 2017;12:102–7.CrossRef Gnant M, Harbeck N, Thomssen C. St. Gallen/Vienna 2017: a brief summary of the consensus discussion about escalation and de-escalation of primary breast cancer treatment. Breast Care Basel. 2017;12:102–7.CrossRef
9.
Zurück zum Zitat Ali HR, Provenzano E, Dawson SJ, et al. Association between CD8 + T cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol. 2014;25:1536–43.CrossRefPubMed Ali HR, Provenzano E, Dawson SJ, et al. Association between CD8 + T cell infiltration and breast cancer survival in 12,439 patients. Ann Oncol. 2014;25:1536–43.CrossRefPubMed
10.
Zurück zum Zitat Bense RD, Sotiriou C, Piccart-Gebhart MJ, et al. Relevance of tumor-infiltrating immune cell composition and functionality for disease outcome in breast cancer. J Natl Cancer Inst. 2016;109:djw192. Print January 2017. Bense RD, Sotiriou C, Piccart-Gebhart MJ, et al. Relevance of tumor-infiltrating immune cell composition and functionality for disease outcome in breast cancer. J Natl Cancer Inst. 2016;109:djw192. Print January 2017.
11.
Zurück zum Zitat Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26:259–71.CrossRefPubMed Salgado R, Denkert C, Demaria S, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26:259–71.CrossRefPubMed
12.
Zurück zum Zitat Hendry S, Salgado R, Gevaert T, et al. Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in melanoma, gastrointestinal tract carcinomas, non-small cell lung carcinoma and mesothelioma, endometrial and ovarian carcinomas, squamous cell carcinoma of the head and neck, genitourinary carcinomas, and primary brain tumors. Adv Anat Pathol. 2017;24:311–35.CrossRefPubMed Hendry S, Salgado R, Gevaert T, et al. Assessing tumor-infiltrating lymphocytes in solid tumors: a practical review for pathologists and proposal for a standardized method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in melanoma, gastrointestinal tract carcinomas, non-small cell lung carcinoma and mesothelioma, endometrial and ovarian carcinomas, squamous cell carcinoma of the head and neck, genitourinary carcinomas, and primary brain tumors. Adv Anat Pathol. 2017;24:311–35.CrossRefPubMed
13.
Zurück zum Zitat Swisher SK, Wu Y, Castaneda CA, et al. Interobserver agreement between pathologists assessing tumor-infiltrating lymphocytes (TILs) in breast cancer using methodology proposed by the International TILs Working Group. Ann Surg Oncol. 2016;23:2242–8.CrossRefPubMed Swisher SK, Wu Y, Castaneda CA, et al. Interobserver agreement between pathologists assessing tumor-infiltrating lymphocytes (TILs) in breast cancer using methodology proposed by the International TILs Working Group. Ann Surg Oncol. 2016;23:2242–8.CrossRefPubMed
14.
Zurück zum Zitat Kashiwagi S, Asano Y, Goto W, et al. Use of tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer. PLoS One. 2017;12:e0170634.CrossRefPubMedPubMedCentral Kashiwagi S, Asano Y, Goto W, et al. Use of tumor-infiltrating lymphocytes (TILs) to predict the treatment response to eribulin chemotherapy in breast cancer. PLoS One. 2017;12:e0170634.CrossRefPubMedPubMedCentral
15.
Zurück zum Zitat Park HS, Heo I, Kim JY, Kim S, Nam S, Park S, Kim SI. No effect of tumor-infiltrating lymphocytes (TILs) on prognosis in patients with early triple-negative breast cancer: validation of recommendations by the International TILs Working Group 2014. J Surg Oncol. 2016;114:17–21.CrossRefPubMed Park HS, Heo I, Kim JY, Kim S, Nam S, Park S, Kim SI. No effect of tumor-infiltrating lymphocytes (TILs) on prognosis in patients with early triple-negative breast cancer: validation of recommendations by the International TILs Working Group 2014. J Surg Oncol. 2016;114:17–21.CrossRefPubMed
16.
Zurück zum Zitat Kwon HJ, Choi JE, Kang SH, Son Y, Bae YK. Prognostic significance of CD9 expression differs between tumour cells and stromal immune cells, and depends on the molecular subtype of the invasive breast carcinoma. Histopathology. 2017;70:1155–65.CrossRefPubMed Kwon HJ, Choi JE, Kang SH, Son Y, Bae YK. Prognostic significance of CD9 expression differs between tumour cells and stromal immune cells, and depends on the molecular subtype of the invasive breast carcinoma. Histopathology. 2017;70:1155–65.CrossRefPubMed
17.
Zurück zum Zitat Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784–95.CrossRefPubMedPubMedCentral Hammond ME, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784–95.CrossRefPubMedPubMedCentral
18.
Zurück zum Zitat Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4013.CrossRefPubMed Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4013.CrossRefPubMed
19.
Zurück zum Zitat Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24:2206–23.CrossRefPubMedPubMedCentral Goldhirsch A, Winer EP, Coates AS, et al. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013;24:2206–23.CrossRefPubMedPubMedCentral
20.
Zurück zum Zitat Kotoula V, Chatzopoulos K, Lakis S, et al. Tumors with high-density tumor-infiltrating lymphocytes constitute a favorable entity in breast cancer: a pooled analysis of four prospective adjuvant trials. Oncotarget. 2016;7:5074–87.CrossRefPubMed Kotoula V, Chatzopoulos K, Lakis S, et al. Tumors with high-density tumor-infiltrating lymphocytes constitute a favorable entity in breast cancer: a pooled analysis of four prospective adjuvant trials. Oncotarget. 2016;7:5074–87.CrossRefPubMed
21.
Zurück zum Zitat Ruffell B, Au A, Rugo HS, Esserman LJ, Hwang ES, Coussens LM. Leukocyte composition of human breast cancer. Proc Natl Acad Sci USA. 2012;109:2796–801.CrossRefPubMed Ruffell B, Au A, Rugo HS, Esserman LJ, Hwang ES, Coussens LM. Leukocyte composition of human breast cancer. Proc Natl Acad Sci USA. 2012;109:2796–801.CrossRefPubMed
22.
Zurück zum Zitat Wein L, Savas P, Luen SJ, Virassamy B, Salgado R, Loi S. Clinical validity and utility of tumor-infiltrating lymphocytes in routine clinical practice for breast cancer patients: current and future directions. Front Oncol. 2017;7:156.CrossRefPubMedPubMedCentral Wein L, Savas P, Luen SJ, Virassamy B, Salgado R, Loi S. Clinical validity and utility of tumor-infiltrating lymphocytes in routine clinical practice for breast cancer patients: current and future directions. Front Oncol. 2017;7:156.CrossRefPubMedPubMedCentral
23.
Zurück zum Zitat Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8 + lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29:1949–55.CrossRefPubMed Mahmoud SM, Paish EC, Powe DG, et al. Tumor-infiltrating CD8 + lymphocytes predict clinical outcome in breast cancer. J Clin Oncol. 2011;29:1949–55.CrossRefPubMed
24.
Zurück zum Zitat Rathore AS, Goel MM, Makker A, Kumar S, Srivastava AN. Is the tumor-infiltrating natural killer cell (NK-TILs) count in infiltrating ductal carcinoma of breast prognostically significant?. Asian Pac J Cancer Prev. 2014;15:3757–61.CrossRefPubMed Rathore AS, Goel MM, Makker A, Kumar S, Srivastava AN. Is the tumor-infiltrating natural killer cell (NK-TILs) count in infiltrating ductal carcinoma of breast prognostically significant?. Asian Pac J Cancer Prev. 2014;15:3757–61.CrossRefPubMed
25.
Zurück zum Zitat Gu-Trantien C, Loi S, Garaud S, et al. CD4(+) follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 2013;123:2873–92.CrossRefPubMedPubMedCentral Gu-Trantien C, Loi S, Garaud S, et al. CD4(+) follicular helper T cell infiltration predicts breast cancer survival. J Clin Invest. 2013;123:2873–92.CrossRefPubMedPubMedCentral
26.
Zurück zum Zitat Ingold Heppner B, Loibl S, Denkert C. Tumor-infiltrating lymphocytes: a promising biomarker in breast cancer. Breast Care Basel. 2016;11:96–100.CrossRefPubMedPubMedCentral Ingold Heppner B, Loibl S, Denkert C. Tumor-infiltrating lymphocytes: a promising biomarker in breast cancer. Breast Care Basel. 2016;11:96–100.CrossRefPubMedPubMedCentral
27.
Zurück zum Zitat Dushyanthen S, Beavis PA, Savas P, et al. Relevance of tumor-infiltrating lymphocytes in breast cancer. BMC Med. 2015;13:202,015-0431–3. Dushyanthen S, Beavis PA, Savas P, et al. Relevance of tumor-infiltrating lymphocytes in breast cancer. BMC Med. 2015;13:202,015-0431–3.
28.
Zurück zum Zitat Schmid P, Cruz C, Braiteh FS, et al. Atezolizumab in metastatic TNBC (mTNBC): long-term clinical outcomes and biomarker analyses. Cancer Res Proc AACR Ann Meeting. 2017;77:2986. Schmid P, Cruz C, Braiteh FS, et al. Atezolizumab in metastatic TNBC (mTNBC): long-term clinical outcomes and biomarker analyses. Cancer Res Proc AACR Ann Meeting. 2017;77:2986.
29.
Zurück zum Zitat Ravelli A, Roviello G, Cretella D, et al. Tumor-infiltrating lymphocytes and breast cancer: beyond the prognostic and predictive utility. Tumour Biol. 2017;39:1010428317695023.CrossRefPubMed Ravelli A, Roviello G, Cretella D, et al. Tumor-infiltrating lymphocytes and breast cancer: beyond the prognostic and predictive utility. Tumour Biol. 2017;39:1010428317695023.CrossRefPubMed
Metadaten
Titel
Prognostic Value of Tumor-Infiltrating Lymphocyte Density Assessed Using a Standardized Method Based on Molecular Subtypes and Adjuvant Chemotherapy in Invasive Breast Cancer
verfasst von
Nuri Jang, MD
Hee Jung Kwon, MD
Min Hui Park, BS
Su Hwan Kang, MD
Young Kyung Bae, MD, PhD
Publikationsdatum
12.01.2018
Verlag
Springer International Publishing
Erschienen in
Annals of Surgical Oncology / Ausgabe 4/2018
Print ISSN: 1068-9265
Elektronische ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-017-6332-2

Weitere Artikel der Ausgabe 4/2018

Annals of Surgical Oncology 4/2018 Zur Ausgabe

Mehr Frauen im OP – weniger postoperative Komplikationen

21.05.2024 Allgemeine Chirurgie Nachrichten

Ein Frauenanteil von mindestens einem Drittel im ärztlichen Op.-Team war in einer großen retrospektiven Studie aus Kanada mit einer signifikanten Reduktion der postoperativen Morbidität assoziiert.

„Übersichtlicher Wegweiser“: Lauterbachs umstrittener Klinik-Atlas ist online

17.05.2024 Klinik aktuell Nachrichten

Sie sei „ethisch geboten“, meint Gesundheitsminister Karl Lauterbach: mehr Transparenz über die Qualität von Klinikbehandlungen. Um sie abzubilden, lässt er gegen den Widerstand vieler Länder einen virtuellen Klinik-Atlas freischalten.

Was nützt die Kraniektomie bei schwerer tiefer Hirnblutung?

17.05.2024 Hirnblutung Nachrichten

Eine Studie zum Nutzen der druckentlastenden Kraniektomie nach schwerer tiefer supratentorieller Hirnblutung deutet einen Nutzen der Operation an. Für überlebende Patienten ist das dennoch nur eine bedingt gute Nachricht.

Klinikreform soll zehntausende Menschenleben retten

15.05.2024 Klinik aktuell Nachrichten

Gesundheitsminister Lauterbach hat die vom Bundeskabinett beschlossene Klinikreform verteidigt. Kritik an den Plänen kommt vom Marburger Bund. Und in den Ländern wird über den Gang zum Vermittlungsausschuss spekuliert.

Update Chirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

S3-Leitlinie „Diagnostik und Therapie des Karpaltunnelsyndroms“

Karpaltunnelsyndrom BDC Leitlinien Webinare
CME: 2 Punkte

Das Karpaltunnelsyndrom ist die häufigste Kompressionsneuropathie peripherer Nerven. Obwohl die Anamnese mit dem nächtlichen Einschlafen der Hand (Brachialgia parästhetica nocturna) sehr typisch ist, ist eine klinisch-neurologische Untersuchung und Elektroneurografie in manchen Fällen auch eine Neurosonografie erforderlich. Im Anfangsstadium sind konservative Maßnahmen (Handgelenksschiene, Ergotherapie) empfehlenswert. Bei nicht Ansprechen der konservativen Therapie oder Auftreten von neurologischen Ausfällen ist eine Dekompression des N. medianus am Karpaltunnel indiziert.

Prof. Dr. med. Gregor Antoniadis
Berufsverband der Deutschen Chirurgie e.V.

S2e-Leitlinie „Distale Radiusfraktur“

Radiusfraktur BDC Leitlinien Webinare
CME: 2 Punkte

Das Webinar beschäftigt sich mit Fragen und Antworten zu Diagnostik und Klassifikation sowie Möglichkeiten des Ausschlusses von Zusatzverletzungen. Die Referenten erläutern, welche Frakturen konservativ behandelt werden können und wie. Das Webinar beantwortet die Frage nach aktuellen operativen Therapiekonzepten: Welcher Zugang, welches Osteosynthesematerial? Auf was muss bei der Nachbehandlung der distalen Radiusfraktur geachtet werden?

PD Dr. med. Oliver Pieske
Dr. med. Benjamin Meyknecht
Berufsverband der Deutschen Chirurgie e.V.

S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“

Appendizitis BDC Leitlinien Webinare
CME: 2 Punkte

Inhalte des Webinars zur S1-Leitlinie „Empfehlungen zur Therapie der akuten Appendizitis bei Erwachsenen“ sind die Darstellung des Projektes und des Erstellungswegs zur S1-Leitlinie, die Erläuterung der klinischen Relevanz der Klassifikation EAES 2015, die wissenschaftliche Begründung der wichtigsten Empfehlungen und die Darstellung stadiengerechter Therapieoptionen.

Dr. med. Mihailo Andric
Berufsverband der Deutschen Chirurgie e.V.