Effective Therapeutic Strategy For Breast Cancer Research Articles

CXCL16/CXCR6 chemokine signaling mediates breast cancer progression by pERK1/2-dependent mechanisms.

Our previous studies demonstrate that CXCL6/CXCR6 chemokine axis induces prostate cancer progression by the AKT/mTOR signaling pathway; however, its role and mechanisms underlying invasiveness and metastasis of breast cancer are yet to be elucidated. In this investigation, CXCR6 protein expression was examined using high-density tissue microarrays and immunohistochemistry. Expression of CXCR6 shows a higher epithelial staining in breast cancer nest site and metastatic lymph node than the normal breast tissue, suggesting that CXCR6 may be involved in breast cancer (BC) development. In vitro and in vivo experiments indicate that overexpression of CXCR6 in BC cells has a marked effect on increasing cell migration, invasion and metastasis. In contrast, reduction of CXCR6 expression by shRNAs in these cells greatly reduce its invasion and metastasis ability. Mechanistic analyses show that CXCL16/CXCR6 chemokine axis is capable of modulating activation of RhoA through activating ERK1/2 signaling pathway, which then inhibits the activity of cofilin, thereby enhancing the stability of F-actin, responsible for invasiveness and metastasis of BC. Taken together, our data shows for the first time that the CXCR6 / ERK1/2/ RhoA / cofilin /F-actin pathway plays a central role in the development of BC. Targeting the signaling pathway may prove beneficial to prevent metastasis and provide a more effective therapeutic strategy for BC.

A pilot feasibility study to evaluate the efficacy of lapatinib in eliminating HER2-positive tumor cells circulating in peripheral blood of women with metastatic breast cancer.

e22105 Background: EGFR and HER2 are expressed on CTCs from pts with breast cancer (BC). In this study we aimed to evaluate the efficacy of lapatinib, a dual EGFR and HER2 TK inhibitor, to eliminate HER2+ CTCs in metastatic BC. Methods: Pts with metastatic disease and HER2+ CTCs detected after disease stabilization or response to prior therapy were eligible. Pts received lapatinib till disease or CTC progression, whichever occurred first. Cytospins of peripheral blood mononuclear cells (PBMCs) were double stained with HER2 or EGFR along with cytokeratin antibody; 106 PBMCs/pt were analyzed for each molecule. Results: Twenty-two pts were enrolled; median age was 62.5 yrs, 2 had HER2+ primary, 12 (54.5%) had visceral disease and 8 (36.4%) had received ≥3 lines. Treatment was discontinued in 1 pt before the end of the 1st cycle due to toxicity and 1 withdrew consent after 3 cycles. A total of 119 courses were administered [median 4.0 (range, 0.5-26.0)]; disease evaluation revealed SD in 11 pts and PD in 10. HER2+ CTC counts declined in 18 (85.7%) pts during treatment [median time to nadir 1 mo (range, 1 – 5)]. After the 1st cycle, HER2+ CTCs decreased in 14 (66.7%) pts, increased in 6 (28.6%) and remained stable in 1 (4.7%). At baseline, 3444 HER2+ CTCs were detected (median 130), whereas after the 1st and 2nd cycles, 2281 (median 1) and 989 (median 2), respectively, were identified. The difference between baseline and post-1st or post-2nd cycle CTC counts was significant for all pts and for patients with SD but not in progressing pts. EGFR expression on CTCs was evaluated at the baseline and the end of treatment sample; in 6 of 8 pts with CTCs detected at both time points, the % EGFR+ CTCs/pt increased from a mean of 29.72% to 71.52%. Moreover, the % ratio of EGFR+ among the total CTCs increased from 17.08% to 37.59%. Conclusions: Lapatinib is effective in decreasing HER2+ CTCs in pts with metastatic BC, irrespective of the HER2 status of the primary. EGFR+ CTCs increase during treatment implicating EGFR as a possible resistance mechanism. The above results suggest that tailoring therapy according to targets present on CTCs represents an effective therapeutic strategy in BC. Clinical trial information: NCT00694252.

Abstract 3411: A pilot feasibility study to evaluate the efficacy of lapatinib in the elimination of HER2-positive circulating tumor cells in peripheral blood of women with metastatic breast cancer

Abstract Background: The monitoring of circulating tumor cells (CTCs) detected in peripheral blood (PB) of patients (pts) with metastatic breast cancer (BC) has been proven a potent prognostic tool. CTCs detected after the completion of therapy are theoretically chemo- and/or hormone-resistant and could lead to disease progression. EGFR and HER2 expression has been demonstrated in CTCs from pts with BC. In the present trial we aimed to evaluate the efficacy of lapatinib, a dual EGFR and HER2 tyrosine kinase inhibitor, in eliminating HER2 positive (+) CTCs of women with metastatic BC. Pts and methods: Pts with metastatic BC and HER2+ CTCs detected despite disease stabilization or response after the completion of prior therapy were eligible. Pts received lapatinib, 1500 mg/day orally till disease or CTC progression, whichever occurred first. HER2 expression was evaluated in cytospins of peripheral blood mononuclear cells’ (PBMCs) prepared from PB obtained at baseline and monthly thereafter. Cytospins were stained with HER2 along with cytokeratin antibody; a total of 10^6 PBMCs/pt were analyzed by double immunofluorescence. Results: Nineteen pts were enrolled from September 2008 to October 2011. Median age was 62 years, 12 (63.2%) pts were post-menopausal and 2 had HER2+ tumors. Twelve (63.2%) pts had visceral disease and 7 (36.8%) had received β3 lines of treatment. One pt discontinued treatment prior to the completion of the first cycle due to toxicity and 2 pts are not evaluable yet. The median duration of treatment was 4.0 (range, 0.5 - 34.0) months (mo). CTC counts declined in 15 out of 16 pts during treatment with a maximum percentage of decrease of 100% in all of them. The median time to and the median duration of nadir CTC counts were 1 mo (range, 1 - 3 mo) and 1 mo (range, 0 - 7 mo), respectively. Prior to the second treatment cycle, a decrease in CTC counts was observed in 14 (88%) pts, in 1 (7%) the CTC count increased by 33% and in 1 (7%) remained stable. Median percentage of CTC count decrease per pt was 100% (range, 45-100%). At baseline, a total of 2642 HER2+ CTCs were detected (median: 79/pt, range 2 - 617), whereas after the completion of first cycle a total of 430 HER2+ CTCs were identified (median: 0, range 0 - 223). Disease evaluation revealed stable disease in 5 pts and progressive disease in 11. In pts with stable disease a sustained decrease in CTC counts over 2 to 7 mo was observed. On the contrary, in 9 out of 11 pts with disease progression, the decrease in CTC counts was short-lasting (median 1.0 mo, range 0 - 4). Conclusions: Lapatinib is effective in decreasing HER2+ CTCs in pts with metastatic BC, irrespective of the HER2 status of the primary tumor. Sustained CTC reduction was associated with disease stabilization. The above results suggest that tailoring therapy according to targets present on CTCs could be an effective therapeutic strategy in BC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3411. doi:1538-7445.AM2012-3411