Clinical Research Papers:

Tumors with high-density tumor infiltrating lymphocytes constitute a favorable entity in breast cancer: a pooled analysis of four prospective adjuvant trials

Vassiliki Kotoula _, Kyriakos Chatzopoulos, Sotiris Lakis, Zoi Alexopoulou, Eleni Timotheadou, Flora Zagouri, George Pentheroudakis, Helen Gogas, Eleni Galani, Ioannis Efstratiou, Thomas Zaramboukas, Angelos Koutras, Gerasimos Aravantinos, Epaminontas Samantas, Amanda Psyrri, Helen Kourea, Mattheos Bobos, Pavlos Papakostas, Paris Kosmidis, Dimitrios Pectasides and George Fountzilas

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Oncotarget. 2016; 7:5074-5087. https://doi.org/10.18632/oncotarget.6231

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Vassiliki Kotoula1,2, Kyriakos Chatzopoulos2, Sotiris Lakis2, Zoi Alexopoulou3, Eleni Timotheadou4, Flora Zagouri5, George Pentheroudakis6, Helen Gogas7, Eleni Galani8, Ioannis Efstratiou9, Thomas Zaramboukas9, Angelos Koutras10, Gerasimos Aravantinos11, Epaminontas Samantas12, Amanda Psyrri13, Helen Kourea14, Mattheos Bobos2, Pavlos Papakostas15, Paris Kosmidis16, Dimitrios Pectasides17 and George Fountzilas2

1 Department of Pathology, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

2 Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Thessaloniki, Greece

3 Health Data Specialists Ltd, Department of Biostatistics, Athens, Greece

4 Department of Medical Oncology, “Papageorgiou” Hospital , Thessaloniki, Greece

5 Department of Clinical Therapeutics, “Alexandra” Hospital, Athens, Greece

6 Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

7 First Department of Medicine, “Laiko” General Hospital, Athens, Greece

8 Second Department of Medical Oncology, “Metropolitan” Hospital, Piraeus, Greece

9 Department of Pathology, “Papageorgiou” Hospital, Thessaloniki, Greece

10 Division of Oncology, Department of Medicine, University Hospital, Patras, Greece

11 Second Department of Medical Oncology, “Agii Anargiri” Cancer Hospital, Athens, Greece

12 Third Department of Medical Oncology, “Agii Anargiri” Cancer Hospital, Athens, Greece

13 Division of Oncology, Second Department of Internal Medicine, Attikon University Hospital, Athens, Greece

14 Department of Pathology, University Hospital of Patras, Rion, Greece

15 Oncology Unit, “Hippokration” Hospital, Athens, Greece

16 Second Department of Medical Oncology, Hygeia Hospital, Athens, Greece

17 Oncology Section, Second Department of Internal Medicine, “Hippokration” Hospital, Athens, Greece

Correspondence to:

Vassiliki Kotoula, email:

Keywords: breast cancer, tumor infiltrating lymphocytes, clinical breast cancer subtypes, trastuzumab, prognostic

Received: April 15, 2015 Accepted: October 09, 2015 Published: October 25, 2015


Background: Tumor infiltrating lymphocytes (TILs) are considered in the prognosis of breast cancer (BC) patients. Here, we investigated the prognostic/predictive effect of TILs in patients treated in the frame of four prospective trials with adjuvant anthracycline-based chemotherapy in the pre- and post-trastuzumab era.

Methods: TILs density was histologically assessed as percentage of stromal area on whole routine sections of 2613 BC (1563 Luminal A/B; 477 Luminal HER2; 246 HER2-enriched; 327 triple negative [TNBC]) and were evaluated as high/low at three cut-offs (c/o; 50% [lymphocytic predominance, LP], 35% and 25%), in separate training and validation sets.

Results: High TILs were present in 3.5%, 6.5% and 11.5% of all tumors, using the 50%, 35% and 25% c/o, respectively. TILs status did not interact with BC subtypes or trastuzumab treatment. LPBC patient outcome was not affected by nodal status, while high TILs were favorable in TNBC with unfavorable nodal status. When adjusted for standard clinicopathological parameters and treatment, high TILs independently predicted for favorable outcome, e.g., disease-free survival with the 35% c/o in the entire cohort (HR = 0.44, 95% CI 0.28-0.69, p < 0.001) and in specific subtypes.

Conclusions: High TILs tumors, especially LPBC seem worthy validating as a separate entity of favorable prognosis in breast cancer.

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