Clinical studies suggest that triple negative breast cancer (TNBC) patients with epidermal growth factor receptor (EGFR)-expressing tumors could benefit from therapy withCetuximab, which targets EGFR. NK cells are the primary effectors of antibody (Ab)-dependent cell-mediated cytotoxicity (ADCC) and thus play a role in Ab-based therapies. We have previously described diminished levels of Cetuximab-mediated ADCC in vitro in patients with advanced breast cancer. Here, we investigated the potential causes of this NK-cell functional deficiency. We characterized NK-cell activating/inhibitory receptors in the peripheral blood of breast cancer patients and found CD85j inhibitory receptor overexpression. The capacity of NK cells to perform Cetuximab-triggered ADCC against TNBC cells correlated inversely with CD85j expression, even in the presence of the stimulatory cytokines IL-2 or IL-15. Hence, patients expressing high levels of CD85j had an impaired ability to lyse TNBC cells in the presence of Cetuximab. We also found that CD85j overexpression was associated with HLA-I and soluble HLA-G expression by tumors. A CD85j functional blockade with a CD85j antagonist Ab restored ADCC levels in breast cancer patients and reverted this negative effect. Our data suggest that strategies that overcome the hurdles of immune activation could improve Cetuximab clinical efficacy.Keywords: ADCC r CD85j r Cetuximab r EGFR r NK cells r Triple negative breast cancer Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction NK cells are a major component of the innate immune system and can limit the growth and dissemination of several types of Correspondence: Dr. Estrella M. Levy e-mail: estrellamlevy@yahoo.com.ar tumors [1]. In cancer immune surveillance, NK cells can exert direct cellular cytotoxicity on tumor cells without prior sensitization and secrete immunostimulatory cytokines such as IFN-γ, which can control both local tumor growth and metastasis [2,3]. Moreover, NK cells act as effectors in Ab-dependent cell-mediated cytotoxicity (ADCC) [4]. Accordingly, it has been determined that NK-cell activity can play a significant role [13]. LIR-1, the most broadly expressed LIR family member, is an inhibitory receptor that binds multiple MHC-I molecules, both classical (HLA-A, -B, and -C) and nonclassical (HLA-E, -F, and -G) [12][13][14][15][16]. The inhibitory receptor LIR-1 (also known as ILT-2 and CD85j) is the only LIR expressed on NK cells [17]. Upon ligand binding, CD85j is able to inhibit NK-cell cytotoxicity [16,[18][19][20], as well as IFN-γ production [21]. Despite the fact that NK-cell inhibitory receptor engagement with target cells is considered a primary event in the formation of the inhibitory synapse and the subsequent prevention of cell lysis [22], CD85j receptor involvement in cancer has been poorly addressed. In lung cancer, CD85j expression was drastically reduced on intratumoral NK cells compared to blood NK cells [23]. In contrast, CD85j was upreg...
PurposeSeveral studies have shown that estrogen receptor (ER) and progesterone receptor (PR) expression and human epidermal growth factor receptor 2 (HER2) expression may vary during tumoral progression. We aimed to describe and compare ER, PR, and HER2 expressions in primary breast tumors and synchronic axillary nodal metastases, and evaluate phenotypic correlations between them.MethodsPatients were identified prospectively through surgical procedures between September 2013 and July 2016. The status of ER, PR, HER2, and Ki-67 were pathologically analyzed in breast cancers and axillary nodal metastases; these patients were classified based on the breast cancer phenotypes into five subgroups.ResultsSynchronic axillary nodal metastases were observed in 127 patients. In breast cancers and nodal metastases, correlation analyses of ER, PR, and Ki-67 expression showed a statistical dependence and concordance between these samples was unambiguously demonstrated through Bland-Altman plots for each determination. Primary breast tumors were classified as follows: luminal A, 41.6%; luminal B, 40.0%; luminal B/HER2, 9.6%; HER2, 2.4%; triple negative, 6.4%. Alterations in phenotype were observed in 28% of patients. The most frequent phenotypic alteration was from luminal B to A (36.4%). Ten cases (30.3%) showed alterations with therapeutic implications; six gained HER2 overexpression, and four, hormonal receptor (HR) expression. A moderate strength of agreement (Cohen's κ coefficient, 0.59; 95% confidence interval, 0.48–0.71) was observed. In multivariate analyses, high histologic grade (odds ratio [OR], 2.79; p<0.047) and high Ki-67 expression (OR, 1.05; p<0.037) were independent factors predictive of phenotypic alterations.ConclusionStrong correlations were observed in HR and Ki-67 expressions between primary breast tumors and axillary nodal metastases, and a moderate concordance was observed in their phenotypical characteristics. Nevertheless, alterations did exist, and one-third of these changes may have therapeutic implications. The nodal metastases of tumors with high grade and high Ki-67 expression may need to be analyzed, to obtain complete therapeutic information.
Introduction: Breast cancer is the tumor with highest incidence and mortality in women in Argentina. Hormonal receptors (HR) and HER2 are the most important prognostic and predictive factors. It is suggested that estrogen receptors (ER), progesterone receptors (PR) and HER2 expression can vary during tumor progression and metastases development. Published evidence has reported discordance between primary tumors and its metastases ranging from 15-54% for HR and HER2 overexpression. A similar discordance situation may exist among primary tumor (PT) and its axillary nodal metastases (NM) Objective: To describe the expression and discordance of ER, PR and HER2 in PT and its synchronic NM Material and methods: Prospective analysis of surgical breast cancer patients (pts) at Instituto Alexander Fleming (Sept 2013 to Feb 2016). HR were analyzed by immunohistochemistry (IHC) according to CAP protocols; values ≥ 10% were considered positive. HER2 overexpression was defined by 3+ IHC or positive FISH. Paired t test was used to compare mean using Prims 5 software. Results: In 587 breast cancer surgeries, 190 pts presented NM. HR and HER2 analysis was performed in 101 paired samples. Median age was 51 years (r 25-83). Mean tumor size was 3,3 ± 0,2 cm. 0,99% (1) were stage I, 68,3% (69) stage II and 30,7% (31) stage III. Most frequent histologic subtype was ductal carcinoma (66.3%). 78.2% presented lymphovascular invasion. Median positive nodes were 2 (r 1-21). Paired samples allowed ER analysis in 99 cases, PR in 98 and HER2 in 96; 8 NM were Her2++; FISH analysis was inconclusive in 4 of them due to insufficient tissue. No differences were observed on ER between PT and NM (72% vs 71.1%, OR: 0,91, IC95 -3.2-5.1; p>0,05), nor PR expression (52.1% vs 54,5%, OR: -2.1, IC95 -7.1-3.01; p>0,05). PT were ER+ in 86.1% of the cases; NM were ER+ in 82.2%. Regarding PR, PT were 74.3% PR+ and NM were 76.2% PR+. 28 of the 101 pts (27.7%) were discordant. 5 pts with ER+ PT had ER- NM, and 3 pts had PT ER- but ER+ NM, representing a 7.9% of discordance. 4 of 75 pts with PR+ in PT were PR- in NM, while 8 of 26 pts were PR- in PT but PR+ in NM. Of the 13 HER2+ pts, 2 (15%) did not present overexpression in NM. On the other hand, 6 (7%) of the 83 HER2- PT were HER2+ in NM. 4 of 9 pts had PT RH and Her2- (TN), but NM RH and/or Her2+. Discussion: Tumor heterogeneity is an important issue that may affect clinical decisions. Axillary nodes are the first metastatic site for breast cancer and different studies have shown discrepancy between PT and NM. We described a discordant expression in ER, PR and HER2 of 8%, 12% and 9% respectively. These differences could be due to technical reasons, intratumor heterogeneity and/or a different cellular phenotype. Although the clinical importance of these changes are not completely understood, NM status could bring important prognostic and therapeutic information defining a particular group of patients in which a specific therapeutic strategy could influence long term results. In fact, in our series 44% of TN tumors presented NM with a therapeutic target, either HR or HER2. We therefore confirm that pathological analysis of NM may bring up additional information that could be useful in a prognostic or therapeutic point of view. Citation Format: Rizzo MM, Mando P, Perez de la Puente C, Maino M, Ponce C, Fabiano V, Pombo MT, Loza CM, Costanzo MV, Nervo A, Nadal J, Colo F, Chacon RD. Her2 and hormonal receptor analysis in breast cancer synchronic node metastases could add therapeutic information [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-09-40.
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