Preclinical and clinical studies showed that the immune system gives a substantial contribution to the therapeutic effects of trastuzumab.91,92 Several studies have recently assessed the prognostic and predictive value of tumor-infiltrating lymphocytes (TILs).93–95 In the neoadjuvant setting, a recent large meta-analysis confirmed the association between pretreatment TIL levels and the probability of achieving pCR in patients with HER2-positive early-stage breast cancer treated with anti-HER2 agents.96 However, no association between TILs and pCR rates according to the type of administered anti-HER2 therapy (single or dual blockade) was observed.96 In the adjuvant setting, data from the FinHER and NCCTG N9831 trials reported conflicting results on the role of TILs in predicting the benefit from trastuzumab.97,98 Hence, the role of TILs as contributors of the immune effects of trastuzumab antitumor activity remains controversial and needs to be further evaluated in patients with HER2-positive early-stage breast cancer.99 Immune gene signatures may be useful in this regard, by giving complementary information and more in depth insights on the immune functional status.99

The conflicting data in this field highlight the urgent need for further translational efforts in this setting from the clinical trials that have investigated the two anti-HER2 agents (ie, neratinib and pertuzumab) that proved to be of added benefit in patients already receiving standard chemotherapy plus trastuzumab for 1 year.

Continue Reading


Matteo Lambertini acknowledges the support from the European Society for Medical Oncology (ESMO) for a Translational Research Fellowship at Institut Jules Bordet. EdA and ML are co-last authors.


EdA received honoraria from Roche and travel grants from Roche and GlaxoSmithKline outside the submitted work. His institution has received research grants from Roche. The other authors report no conflicts of interest in this work.

Hampig Raphael Kourie,1 Elie El Rassy,1 Florian Clatot,2,3 Evandro de Azambuja,4 Matteo Lambertini3,4

1Department of Oncology, Faculty of Medicine, Saint Joseph University, Beirut, Lebanon; 2Department of Medical Oncology and IRON/U1245, Centre Henri Becquerel, Rouen, France; 3Breast Cancer Translational Research Laboratory, 4Department of Medicine, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium


1. Ginsburg O, Bray F, Coleman MP, et al. The global burden of women’s cancers: a grand challenge in global health. Lancet. 2017;389(10071):847–860.

2. Senkus E, Kyriakides S, Ohno S, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015;26(suppl 5):v8–v30.

3. Coates AS, Winer EP, Goldhirsch A, et al. Tailoring therapies-improving the management of early breast cancer: St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2015. Ann Oncol. 2015;26(8):1533–1546.

4. Denduluri N, Somerfield MR, Eisen A, et al. Selection of optimal adjuvant chemotherapy regimens for human epidermal growth factor receptor 2 (HER2)-negative and adjuvant targeted therapy for HER2-positive breast cancers: an American Society of Clinical Oncology Guideline Adaptation of the Cancer Care Ontario Clinical Practice Guideline. J Clin Oncol. 2016;34(20):2416–2427.

5. Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO international consensus guidelines for Advanced Breast Cancer (ABC 3). Breast. 2017;31:244–259.

6. Cardoso F, Costa A, Senkus E, et al. 3rd ESO-ESMO international consensus guidelines for Advanced Breast Cancer (ABC 3). Ann Oncol. 2017;28(1):16–33.

7. Lambertini M, Del Mastro L, Pescio MC, et al. Cancer and fertility preservation: international recommendations from an expert meeting. BMC Med. 2016;14(1):1.

8. Perou CM, Sørlie T, Eisen MB, et al. Molecular portraits of human breast tumours. Nature. 2000;406(6797):747–752.

9. Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235(4785):177–182.

10. Slamon DJ, Godolphin W, Jones LA, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244(4905):707–712.

11. Leyland-Jones B. Trastuzumab: hopes and realities. Lancet Oncol. 2002;3(3):137–144.

12. Del Mastro L, Lambertini M, Bighin C, et al. Trastuzumab as first-line therapy in HER2-positive metastatic breast cancer patients. Expert Rev Anticancer Ther. 2012;12(11):1391–1405.

13. Lambertini M, Pondé NF, Solinas C, de Azambuja E. Adjuvant trastuzumab: a 10-year overview of its benefit. Expert Rev Anticancer Ther. 2017;17(1):61–74.

14. Baselga J, Swain SM. Novel anticancer targets: revisiting ERBB2 and discovering ERBB3. Nat Rev Cancer. 2009;9(7):463–475.

15. Klapper LN, Glathe S, Vaisman N, et al. The ErbB-2/HER2 oncoprotein of human carcinomas may function solely as a shared coreceptor for multiple stroma-derived growth factors. Proc Natl Acad Sci U S A. 1999;96(9):4995–5000.

16. Moasser MM. The oncogene HER2: its signaling and transforming functions and its role in human cancer pathogenesis. Oncogene. 2007;26(45):6469–6487.

17. Nagata Y, Lan K-H, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004;6(2):117–127.

18. Nahta R, Takahashi T, Ueno NT, Hung M-C, Esteva FJ. P27(kip1) down-regulation is associated with trastuzumab resistance in breast cancer cells. Cancer Res. 2004;64(11):3981–3986.

19. Nagy P, Friedländer E, Tanner M, et al. Decreased accessibility and lack of activation of ErbB2 in JIMT-1, a herceptin-resistant, MUC4-expressing breast cancer cell line. Cancer Res. 2005;65(2):473–482.

20. Saal LH, Holm K, Maurer M, et al. PIK3CA mutations correlate with hormone receptors, node metastasis, and ERBB2, and are mutually exclusive with PTEN loss in human breast carcinoma. Cancer Res. 2005;65(7):2554–2559.