Ado-trastuzumab emtansine (T-DM1) in HER2+ advanced breast cancer patients: does pretreatment with pertuzumab matter?

AIM: We evaluated the outcomes of patients treated with ado-trastuzumab emantasine (T-DM1) after first-line pertuzumab/trastuzumab, compared with those receiving a trastuzumab-only-based regimen. PATIENTS & METHODS: Patients who received second-line T-DM1 after pertuzumab/trastuzumab (n = 34) were compared with those who received only trastuzumab (n = 73). RESULTS: Overall response rate was 33.3% in patients with prior pertuzumab and 57.1% in the remaining subjects. Disease control rate was 47 and 43%, respectively, and the clinical benefit rate was 43.3 and 71.1%, respectively. Median progression-free survival was 5.0 and 11.0 months, respectively (hazard ratio: 2.02; 95% CI: 1.14-3.58; p = 0.01). CONCLUSION: Patients treated with T-DM1 who previously received pertuzumab present poorer clinical outcomes compared with those receiving a trastuzumab-only-based regimen in the first-line setting.

Development and evaluation of 89Zr-trastuzumab for clinical applications.

Objectives: Due to the suitable physical characteristics of 89Zr as a PET radionuclide and affinity of Trastuzumab monoclonal antibody against HER2, [89Zr]Zr-Trastuzumab was prepared and went through preclinical evaluations for ultimate human applications. Methods: 89Zr was produced by using 89Y(p,n)89Zr reaction at a 30 MeV cyclotron (radionuclide purity>99.9%, specific activity of 17 GBq/µg). p-SCN-Bn-Deferoxamine (DFO); was conjugated to trastuzumab, followed by labeling with 89Zr in oxalate form at optimized condition. Cell binding, internalization and, radioimmuno-activity assays were studied using HER2+ BT474 and HER2- CHO cell lines. Finally, the biodistribution of the radioimmunoconjugate was assessed in normal and HER2+ BT474 tumor-bearing mice using tissue counting and imaging at different intervals after injection. Also, a woman with HER2-positive metastatic breast cancer under treatment with Herceptin underwent both [89Zr]Zr-Trastuzumab and, [18F]FDG PET/CTs. Results: 89Zr was produced with high radionuclidic and radiochemical purities (>99%) and [89Zr]Zr-DFO-Trastuzumab was prepared with radiochemical purity of >98% and specific activity of 9.85 GBq/µmol. The radioimmunoconjugate was stable both in PBS buffer and in human serum for at least 48 h. The radioimmunoactivity assay demonstrated about 70% of [89Zr]Zr-DFO-Trastuzumab is bound to the BT474 cells at the number of 250×106 cells. Cell binding studies showed that about 28% of radioimmunoconjugate is attached to BT474 cells after 90 min. Internalization studies showed that 50% of [89Zr]Zr-Trastuzumab is internalized to BT474 cells only in 6 h. The biodistribution study of the labeled compound in normal mice demonstrated the same pattern of the monoclonal antibodies which is entirely different from the biodistribution of free 89Zr. Biodistribution and imaging studies in tumor-bearing mice showed the significant uptake values of [89Zr]Zr-Trastuzumab in tumor sites. [89Zr]Zr-Trastuzumab PET/CT revealed metastatic lesions documented previously with [18F]FDG PET/CT scan in a woman with breast cancer who was under treatment with Herceptin. Although the [18F]FDG PET/CT scan had better quality images, the valuable and unique advantage of [89Zr]Zr-Trastuzumab PET/CT is delineating HER2+ metastasis, which is essential in diagnosis and HER2-based treatments. Conclusion: The prepared [89Zr]Zr-Trastuzumab has a high potential radio-pharmaceutical for immune-PET imaging of the patients with HER2+ tumors.

HER2-Positive Breast Cancer Patients with Pre-Treatment Axillary Involvement or Postmenopausal Status Benefit from Neoadjuvant Rather than Adjuvant Chemotherapy Plus Trastuzumab Regimens.

BACKGROUND: No survival benefit has yet been demonstrated for neoadjuvant chemotherapy (NAC) against HER2-positive tumors in patients with early breast cancer (BC). The objective of this study was to compare the prognosis of HER2-positive BC patients treated with NAC to that of patients treated with adjuvant chemotherapy (AC). MATERIALS AND METHODS: We retrospectively analyzed disease-free (DFS) and overall survival (OS) in 202 HER2-positive patients treated with NAC and 701 patients treated with AC. All patients received trastuzumab in addition to chemotherapy. Patient data were weighted by a propensity score to overcome selection bias. RESULTS: After inverse probability of treatment weights (IPTW) adjustment, no difference in DFS (p = 0.3) was found between treatments for the total population. However, after multivariate analysis, an interaction was found between cN status and chemotherapy strategy (IPTW-corrected corrected Hazard ratio cHR = 0.52, 95% CI (0.3-0.9), p interaction = 0.08) and between menopausal status and chemotherapy (CT) strategy (cHR = 0.35, 95%CI (0.18-0.7)) p interaction < 0.01). NAC was more beneficial than AC strategy in cN-positive patients and in postmenopausal patients. Moreover, after IPTW adjustment, the multivariate analysis showed that the neoadjuvant strategy conferred a significant OS benefit (cHR = 0.09, 95%CI [0.02-0.35], p < 0.001). CONCLUSION: In patients with HER2-positive BC, the NAC strategy is more beneficial than the AC strategy, particularly in cN-positive and postmenopausal patients. NAC should be used as a first-line treatment for HER2-positive tumors.

Cytolytic Activity of CAR T Cells and Maintenance of Their CD4+ Subset Is Critical for Optimal Antitumor Activity in Preclinical Solid Tumor Models.

Correlative studies of clinical studies for hematological malignancies have implicated that less differentiated, CD8+-dominant CAR T cell products have greater antitumor activity. Here, we have investigated whether the differentiation status of CAR T cell products affects their antitumor activity in preclinical models of solid tumors. We explored if different activation/expansion protocols, as well as different co-stimulatory domains in the CAR construct, influence the short- and long-term efficacy of CAR T cells against HER2-positive tumors. We generated T cell products that range from the most differentiated (CD28.z; OKT3-antiCD28/RPMI expansion) to the least differentiated (41BB.z; OKT3-RetroNectin/LymphoONE expansion), as judged by cell surface expression of the differentiation markers CCR7 and CD45RA. While the effect of differentiation status was variable with regard to antigen-specific cytokine production, the most differentiated CD28.z CAR T cell products, which were enriched in effector memory T cells, had the greatest target-specific cytolytic activity in vitro. These products also had a greater proliferative capacity and maintained CD4+ T cells upon repeated stimulation in vitro. In vivo, differentiated CD28.z CAR T cells also had the greatest antitumor activity, resulting in complete response. Our results highlight that it is critical to optimize CAR T cell production and that optimal product characteristics might depend on the targeted antigen and/or cancer.

Dual targeting and enhanced cytotoxicity to HER2-overexpressing tumors by immunoapoptotin-armored mesenchymal stem cells.

Mesenchymal stem cells (MSCs) are promising vehicles for the delivery of anticancer agents in cancer therapy. However, the tumor targeting of loaded therapeutics is essential. Here, we explored a dual-targeting strategy to incorporate tumor-tropic MSC delivery with HER2-specific killing by the immunoapoptotin e23sFv-Fdt-tBid generated in our previous studies. The MSC engineering allowed simultaneous immunoapoptotin secretion and bioluminescence detection of the modified MSCs. Systemic administration of the immunoapoptotin-engineered MSCs was investigated in human HER2-reconstituted syngeneic mouse models of orthotopic and metastatic breast cancer, as well as in a xenograft nude mouse model of orthotopic gastric cancer. In vivo dual tumor targeting was confirmed by local accumulation of the bioluminescence-imaged MSCs and persistence of His-immunostained immunoapoptotins in tumor sites. The added tumor preference of MSC-secreted immunoapoptotins resulted in a significantly stronger antitumor effect compared with purified immunoapoptotins and Jurkat-delivered immunoapoptotins. This immunoapoptotin-armored MSC strategy provides a rationale for its use in extended malignancies by combining MSC mobility with redirected immunoapoptotins against a given tumor antigen.

HER2 overexpression a major risk factor for recurrence in pT1a-bN0M0 breast cancer: results from a French regional cohort.

The management of pT1a-bN0M0 breast cancer remains an area of controversy. Data from 714 patients classified as having pT1a-bN0M0 breast cancer and treated, from 1999 to 2004 in the Languedoc-Roussillon France, were analyzed. The human epidermal growth factor receptor 2 (HER2) status analyses were centralized. The objective of this study was to describe the prognosis of pT1a-bN0M0 breast cancer according to HER2 distribution and hormonal status. The median follow-up was 6.4 years. Ten-year overall survival was 94%. HER2 overexpression was observed in 6.1% of the patients. The 10-year prognosis of patients with HER2-positive tumors was worse than that of those with HER2-negative (disease-free survival 73% vs. 89%, P < 0.0001). Tumor size (T1a/T1b) was not a relevant prognostic factor. The co-expression of HER2 with hormonal receptors (HR) was associated with high recurrence at 10 years. In both univariate and multivariate analyses, the most relevant prognostic factor for this population was HER2 amplification. In multivariate analysis, patients with HER2-positive tumors had higher risk of mortality (HR, 3.89; 95% CI, 1.58-9.56). In pT1a-bN0M0 breast cancers, HER2 amplification or overexpression is a risk factor for recurrence. In HER2-positive breast cancers, HR expression is associated with a poor prognosis despite the hormone therapy. For this population, a personalized management may be required.

Brain Metastases of Her2-Positive Breast Cancer: A Case of 34 Months' Remission with Lapatinib plus Capecitabine.

Breast tumors overexpressing Her2 (15% of breast cancers) are particularly at risk for central nervous system parenchymal metastases. Whole-brain irradiation (WBI) is the standard of care of brain metastases (BM), and secondarily, systemic treatment is used in case of progression. We report the case of a patient with Her2-positive breast tumor with BM developed 10 months after the initial diagnosis of cancer. The BM were initially treated with WBI then trastuzumab before a recurrence occurred, which was controlled during 34 months with lapatinib and capecitabine. The treatment was regularly adjusted according to the tolerance and the efficacy in order to obtain the control of systemic and neurological disease and to maintain the patient's quality of life. Studies on new targeted agents and/or new combinations with chemotherapy are ongoing. This suggests a better efficacy of treatment and an increased survival of patients. However, these patients are sometimes in a very poor general condition. In this case, we show that a good evaluation of efficacy and toxicities may allow an adaptation of the sequence and dose of treatment in order to preserve the response to treatment and the quality of life. Indeed, systemic treatments are available in addition to WBI. Therefore, the objective of the management of BM is twofold: survival and quality of life.