HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer.We enrolled patients with metastatic HER2(+) breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m(2) intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4-9), and the median overall survival was 17 months (95% CI: 16-28).This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted.
The combination of irinotecan and etoposide showed modest efficacy in terms of response rate in the refractory setting for patients with metastatic breast cancer.The studied dose and schedule of irinotecan and etoposide is very toxic, with >70% grade 3 or 4 treatment-related adverse events.As single agents, both irinotecan and etoposide have documented activity against breast cancer among patients who have received multiple lines of prior chemotherapy. Irinotecan interacts with topoisomerase I (Topo I) to stabilize its cleavable complex, and etoposide has an analogous interaction with topoisomerase II (Topo II). This stabilization without rapid resealing of the cleavage point results in apoptotic cell death and accounts for the antitumor activity of these agents. Topo II levels may increase after administration of a Topo I inhibitor, thus providing a rationale for combining these agents in practice. Based on preclinical data, we conducted a phase II trial of the Topo I inhibitor irinotecan combined with the Topo II inhibitor etoposide in patients with metastatic breast cancer (MBC).This was a single-arm phase II clinical trial in patients with MBC refractory to prior anthracycline, taxane, and capecitabine therapy. All patients were treated with oral etoposide at 50 mg/day on days 1-14 and intravenous irinotecan at 100mg/m2 on days 1 and 15. Treatment cycles were repeated every 28 days. The primary endpoint was median time to progression. Secondary end points included overall clinical response rate using RECIST criteria and assessing the toxicity and safety profile associated with this combination regimen.We enrolled 31 women with refractory MBC to our trial. Median age was 54 (range, 36-84), with the majority (64%) having hormone receptor positive (HR+) human epidermal growth factor receptor 2 negative (HER2 neg) MBC. Median number of prior therapies was five (range, 3-14). Efficacy was evaluated in 24 patients. Seventeen percent had a partial response, and 38% had stable disease as best response. Median progression-free survival was 9 weeks (range, 3-59). All 31 patients were evaluable for toxicity assessment, and 22 patients (71 %) experienced treatment-related grade 3 or 4 adverse events (AEs; Table 1). The most common grade 3-4 AE was neutropenia. The study was terminated early based on interim analysis assessment that suggested toxicities outweighed the efficacy.Irinotecan and etoposide demonstrated only modest clinical activity and poor tolerability in patients with MBC refractory to anthracycline, taxane, and capecitabine therapy. Further studies testing a lower dose and/or different schedule could be considered given ease of administration and responses seen.
CCR Translation for This Article from HSP90 Inhibition Is Effective in Breast Cancer: A Phase II Trial of Tanespimycin (17-AAG) Plus Trastuzumab in Patients with HER2-Positive Metastatic Breast Cancer Progressing on Trastuzumab
Abstract Background. In observational studies, regular use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with reduced breast cancer risk and disease recurrence with evidence that the benefit is greater in overweight/obese women. This parallels findings that obesity is associated with an increase in proinflammatory processes with possible effects on the breast stroma and extracellular matrix. Methods. To assess if body mass index (BMI kg/m2) alters breast tissue response to NSAIDs, we conducted exploratory analyses of change in breast tissue collagen-associated peptides following 6 months of treatment with the NSAID sulindac (150 mg bid) by BMI category: normal (18.5-24.9 n=6), overweight (25-29.9 n=14) and obese (≥30 n=11). Samples for this study were non-cancer core needle breast biopsies from postmenopausal women with a history of hormone receptor positive breast cancer enrolled to study sulindac effect on breast tissue biomarkers. At completion, 36 of 50 patients underwent baseline biopsy and 31 had sufficient tissue for paired analyses. Tissue collagen-associated peptides were studied using whole slide tissue imaging mass spectrometry proteomics. Individual peptide signals were normalized to total ion current and mean peak intensity per area across the entire biological specimen were used to generate a score per patient. Change in stroma peptides was evaluated by BMI status using the Wilcoxon matched pairs signed rank test. Unsupervised hierarchical clustering and heatmap visualization were used to assess differential expression of the peaks. Results. Approximately, 550 peptide peaks were found by targeted collagen tissue imaging proteomics. Striking differences in response to sulindac were observed by BMI. In overweight patients, 6 peptides related to COL1A1, COL6A1, COL6A3 and VIM on database matching differed significantly before and after sulindac treatment. Three were also altered in obese women. Two of the peptides overlapped 10 peptide changes identified in unstratified analyses reported in a separate submitted abstract on the main effect of sulindac on tissue collagen. Interestingly, these peptides were not altered in patients with normal BMI. In addition, on study 15 patients experienced a decrease in BMI and 12 experienced an increase. Two collagen peptides showed inverse relationships dependent on change in BMI status during the study. Conclusion. Six-month treatment with the non-selective NSAID sulindac was associated with changes in collagen-associated peptide differently by BMI status and by weight change. Our findings are most consistent with changes in post-translational hydroxylated proline modifications of collagen variation in the triple helical region. Ongoing work may provide insights on inflammation/adiposity-associated inflammation and effects on breast tissue collagen. Citation Format: Denys Rujchanarong, Peggi M. Angel, Alison Stopeck, Christina Preece, Pavani Chalasani, Patricia A. Thompson. Evidence that body mass index modifies breast tissue collagen peptide response pattern to treatment with the non-steroidal anti-inflammatory drug sulindac [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-10-05.
PURPOSE To determine the safety, toxicity, and efficacy of direct intratumoral injection of an allogeneic major histocompatibility complex (MHC) class I gene, HLA-B7, in a cationic lipid vector (Allovectin-7; Vical Inc, San Diego, CA) in patients with metastatic melanoma. PATIENTS AND METHODS Seventeen HLA-B7-negative patients were treated with intralesional injection of Allovectin-7. Twelve patients received a single intralesional injection containing 10 micrograms (four patients), 50 micrograms (five patients), or 250 micrograms (three patients) of plasmid DNA. Five patients received two or three injections of 10 micrograms DNA to a single tumor site at 2-week intervals. Tumor biopsies pretherapy and 2 and 4 weeks after gene injection were obtained to determine expression of the plasmid by polymerase chain reaction (PCR), reverse transcriptase (RT)-PCR, flow cytometry, and immunohistochemistry. RESULTS Toxicities were related to technical aspects of the injections or biopsies. These included pain, hemorrhage, pneumothorax, and hypotension. Two patients were hospitalized overnight for observation. Seven patients (50%) had tumor responses insofar as the injected nodule decreased > or = 25% by radiologic or physical examination. One patient with a single site of disease achieved a complete remission. Ninety-three percent of the patients' post-gene therapy biopsies contained HLA-B7 plasmid DNA, mRNA, or protein. CONCLUSION Intratumoral injection of the allogeneic histocompatibility gene, HLA-B7, in a lipid vector can be performed safely at plasmid DNA doses < or = 250 micrograms. The safety profile and biologic activity of this therapy warrants further studies to define the mechanism of action, predictors of response, and antitumor efficacy of this approach.
