No abstract

PST with trastuzumab plus docetaxel and carboplatin achieved promising efficacy, with a good pCR rate and favorable tolerability in stage II or III HER-2-positive breast cancer.

Purpose: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are used to determine human epidermal growth factor receptor-2 (HER-2) status and patient eligibility for trastuzumab therapy. Using FISH and IHC, we analyzed the relationship between pathologic complete response to trastuzumab-based neoadjuvant therapy and level of HER-2 amplification in locally advanced breast cancer. Experimental Design: Breastbiopsies from 93 HER-2^positivepatients treatedwithtrastuzumabbased neoadjuvant therapy were centrally collected and analyzed retrospectively for HER-2 amplification using FISH and HER-2 overexpression using IHC. Tumors were classified by FISH as no, low, or high amplification. Biopsies were reassessed centrally by IHC and graded 0, 1+, 2+, or 3+. Results: HER-2 status of tumor samples as assessed by FISH and IHC correlated: 16 no amplification (11 IHC 1+ and 5 IHC 2+), 27 low amplification (26 IHC 3+ and 1 IHC 2+), and 50 high amplification (all IHC 3+). Trastuzumab-based neoadjuvant therapy achieved pathologic complete response in 35 of 93 (37.6%) tumors. Pathologic complete response rate in low-and high-amplification tumors was significantly higher than in no-amplification tumors (44% versus 6%; P < 0.004). Pathologic complete response rate in high-amplification tumors was significantly higher compared with low-amplification tumors (56% versus 22%; P < 0.005). In the subgroup of low-plus high-amplification tumors, no correlation was found between pathologic complete response rate and IHC score, treatment regimen,Tor N stage, tumor grade, or hormonal receptors. Conclusions: This is the first study to show positive correlation between level of HER-2 amplification assessed by FISH and rate of pathologic complete response to trastuzumab-based neoadjuvant treatment.The human epidermal growth factor receptor-2 (HER-2) gene, which plays an important role in tumor formation and growth processes, is amplified in approximately 20% to 30% of all breast cancers (1, 2). Patients whose tumors overexpress HER-2 are more likely to experience a shorter time to relapse and a significantly lower overall survival rate (1, 2). Treatment with trastuzumab (Herceptin), a recombinant monoclonal antibody against HER-2, results in significant clinical benefits in patients diagnosed with HER-2 -positive disease. In phase II/III trials, trastuzumab significantly improved survival by up to 8.5 months when given as first-line treatment in combination with a taxane (3, 4) in women with HER-2 -positive metastatic breast cancer. In five major adjuvant clinical trials involving >13,000 women with HER-2 -positive early breast cancer, trastuzumab significantly reduced the risk of recurrence and improved overall survival by one third (5 -8).In the neoadjuvant setting, primary systemic therapy with trastuzumab-based combination chemotherapy has also shown clinical benefit in terms of both overall response and pathologic complete response rates (9 -13). The goals of primary systemic therapy are to treat occult system...

Immune checkpoint inhibitors are currently tested in different combinations in patients with advanced hepatocellular carcinoma (HCC). Nivolumab, an anti-PD-1 agent, has gained approval in the second-line setting in the USA. Epigenetic drugs have immune-mediated antitumor effects that may improve the activity of immunotherapy agents. Our aim was to study the therapeutic efficacy of checkpoint inhibitors (anti-CTLA-4 and anti-PD-1 antibodies) in combination with the histone deacetylase inhibitor (HDACi) Belinostat. In a subcutaneous Hepa129 murine HCC model, we demonstrated that Belinostat improves the antitumor activity of anti-CTLA-4 but not of anti-PD-1 therapy. This effect correlated with enhanced IFN-γ production by antitumor T-cells and a decrease in regulatory T-cells. Moreover, the combination induced early upregulation of PD-L1 on tumor antigen-presenting cells and late expression of PD-1 on tumor-infiltrating effector T-cells, suggesting the suitability of PD-1 blockade. Indeed, Belinostat combined with the simultaneous blockade of CTLA-4 and PD-1 led to complete tumor rejection. These results provide a rationale for testing Belinostat in combination with checkpoint inhibitors to enhance their therapeutic activity in patients with HCC.