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Spaghetti plots of mean arterial pressure (MAP) from clinical blood pressure measurements at three time points by study group.

Purpose: 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.Experimental Design: 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/m2 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.Results: 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).Conclusions: 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. Clin Cancer Res; 17(15); 5132–9. ©2011 AACR.

Table showing descriptive statistics for three collagen features (length, width, and straightness) at the baseline measure.

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Supplementary Figure S1: Combined patient population and treatments in the three phase III studies included in the analysis. Supplementary Figure S2: OS (A), DP (B), and DPB (C) stratified by category ({greater than or equal to} or < median) of month 3 sBSAP percent change from baseline. Supplementary Table S1: BTM levels at baseline and at month 3 after bone antiresorptive treatment. Supplementary Table S2: Covariate analysis of OS, DP, and DPB at month 3 adjusted for baseline visceral metastases, bone metastases, or ECOG category.

Purpose:To evaluate the effect of sulindac, a nonselective anti-inflammatory drug (NSAID), for activity to reduce breast density (BD), a risk factor for breast cancer.Experimental Design:An open-label phase II study was conducted to test the effect of 12 months' daily sulindac at 150 mg twice daily on change in percent BD in postmenopausal hormone receptor–positive breast cancer patients on aromatase inhibitor (AI) therapy. Change in percent BD in the contralateral, unaffected breast was measured by noncontrast magnetic resonance imaging (MRI) and reported as change in MRI percent BD (MRPD). A nonrandomized patient population on AI therapy (observation group) with comparable baseline BD was also followed for 12 months. Changes in tissue collagen after 6 months of sulindac treatment were explored using second-harmonic generated microscopy in a subset of women in the sulindac group who agreed to repeat breast biopsy.Results:In 43 women who completed 1 year of sulindac (86% of those accrued), relative MRPD significantly decreased by 9.8% [95% confidence interval (CI), −14.6 to −4.7] at 12 months, an absolute decrease of −1.4% (95% CI, −2.5 to −0.3). A significant decrease in mean breast tissue collagen fiber straightness (P = 0.032), an investigational biomarker of tissue inflammation, was also observed. MRPD (relative or absolute) did not change in the AI-only observation group (N = 40).Conclusions:This is the first study to indicate that the NSAID sulindac may reduce BD. Additional studies are needed to verify these findings and determine if prostaglandin E2 inhibition by NSAIDs is important for BD or collagen modulation.

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

Purpose: Bone antiresorptive agents can significantly reduce bone turnover markers (BTM) in patients with advanced cancer. We evaluated association of changes in BTMs with overall survival (OS), disease progression (DP), and disease progression in bone (DPB) in patients with advanced cancer and bone metastases following denosumab or zoledronic acid treatment.Experimental Design: This is an integrated analysis of patient-level data from three identically designed, blinded, phase III trials with patients randomized to subcutaneous denosumab or intravenous zoledronic acid. Levels of the BTMs urinary N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (sBSAP) measured at study entry and month 3 were analyzed. OS, DP, and DPB were compared in patients with BTMs ≥ median versus < median based on month 3 assessments.Results: uNTx levels ≥ the median of 10.0 nmol/mmol at month 3 were associated with significantly reduced OS compared with levels < median (HR for death, 1.85; P < 0.0001). sBSAP levels ≥ median of 12.6 ng/mL were associated with significantly reduced OS compared with levels < median (HR, 2.44; P < 0.0001). uNTx and sBSAP levels ≥ median at month 3 were associated with significantly greater risk of DP (HR, 1.31; P < 0.0001 and HR, 1.71; P < 0.0001, respectively) and DPB (HR, 1.11; P = 0.0407 and HR, 1.27; P < 0.0001, respectively).Conclusions: BTM levels ≥ median after 3 months of bone antiresorptive treatment were associated with reduced OS and increased risk of DP and DPB. Assessment of uNTx and sBSAP levels after bone antiresorptive therapy may add to identification of patients at risk for worse clinical outcomes. Clin Cancer Res; 22(23); 5713–21. ©2016 AACR.

Background: The anti-RANKL monoclonal antibody denosumab has been demonstrated to be superior to the bisphosphonate zoledronate in preventing skeletal-related events (SREs) among patients with incident bone metastases (BMs) from solid tumors (STs), including breast cancer. Clinical guidelines recommend the use of a bone-targeting agent for SRE prevention for ≥2 years. However, the denosumab treatment duration is often 2 clinic visits per month (Table). Univariate analyses showed a positive correlation between increased SRE risk and prior SREs, while they revealed an inverse relationship between increased SRE risk and longer durations of denosumab. Conclusion: Shorter denosumab treatment duration, prior SREs, and higher number of clinic visits are top-ranked risk factors associated with SREs after discontinuation of denosumab treatment in patients with BMs from STs, including breast cancer. A machine learning approach to SRE risk factor identification may help clinicians assess the risks of discontinuing denosumab treatment and improve clinical outcomes for patients with BMs from breast cancer. SHAP Risk Factors That Increase SRE Risk 3-12 Months After Denosumab Cessation in Patients With BMsDenosumab therapy decisions: denosumab duration ≤8 months, time to denosumab initiation ≤2 months after BM diagnosisPrior SREs: ≥2 cumulative number of SREs since baseline up to cessationa, SRE occurrence (from denosumab initiation to cessation)Comorbidities: patients with anxietyVisits: >2 average number of visits per month (hospitalization, emergency room, and other visits [excluding nonphysician interaction]), ≥1 hospitalization, ≥1 emergency room visitaBaseline was defined as 180 days before the date of initial BM diagnosis. BM, bone metastasis; SHAP, Shapley Additive Explanations; SRE, skeletal-related event Citation Format: Alison Stopeck, Celestia Higano, David Henry, Basia Bachmann, Marko Rehn, Dionna Jacobson, Benoit Cadieux, Hossam Saad. A machine learning approach to identify risk factors associated with skeletal-related events following denosumab cessation among patients with bone metastases from breast cancer [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 P1-20-02.

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.

Background: The phase IB/II clinical trial of tucatinib, palbociclib and letrozole (NCT03054363) showed activity in heavily pretreated patients (pts) with HR+/HER2+ metastatic breast cancer (Shagisultanova et. al, Cancer Res 2021:81(4), PS10-03). Here we report an exploratory analysis of intracranial efficacy in enrolled pts with central nervous system metastases (CNS MTS). Methods: Pts with HR+/HER2+ metastatic breast cancer previously treated with at least 2 HER2-targeted agents were enrolled in this phase IB/II clinical trial. Pts with untreated asymptomatic or treated stable CNS MTS were allowed. Efficacy was assessed using RANO-BM and RECIST1.1 criteria based on investigator assessment. CNS progression free survival (CNS-PFS), defined as intracranial progression or death, and bi-compartmental PFS (CNS and/or non-CNS progression or death) were evaluated; best confirmed CNS responses were summarized. Results: The study enrolled 15 pts with CNS MTS: 2 pts had untreated asymptomatic CNS MTS; 12 patients had treated stable CNS MTS; 1 pt had resection of a solitary CNS MTS prior to initiation of study treatment; this pt subsequently had no evidence of CNS disease for 24 months on study. Among 14 pts with evaluable disease, 13 had stable disease (SD) - 6 for ≥6 months, 7 for Citation Format: Elena Shagisultanova, William Gradishar, Ursa Brown-Glaberman, Pavani Chalasani, Andrew Brenner, Alison Stopeck, Jose Mayordomo, Jennifer Diamond, Peter Kabos, Virginia F. Borges. Intracranial efficacy of tucatinib, palbociclib and letrozole combination in patients with HR+/HER2+ breast cancer and brain metastases [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 P1-18-26.

Immune checkpoint inhibitors (ICI) have shown limited response in breast cancers, especially the hormone receptor (HR) positive/human epidermal growth factor receptor 2-negative (Her2-) subtype that is considered to be ‘immunologically cold’ in comparison to the TNBC and Her2+ subtypes. Results from Keynote-028 study showed a ORR of 12% to anti-PD1 antibody, pembrolizumab (KEYTRUDA®; PEM) in previously treated HR+/HER2-/programmed death ligand 1-positive (PD-L1-positive) advanced breast cancer patients. With limited options available for these patients, there is a significant unmet need to expand the clinical benefit from ICI to increased numbers of patients. Imprime PGG (Imprime) is a novel beta glucan acting as a pathogen-associated molecular pattern (PAMP) that drives a cascade of immune activating events. Imprime treatment repolarizes the immunosuppressive microenvironment, activates the maturation of antigen presenting cells, and has significantly enhanced the efficacy of ICI therapy in several preclinical tumor models. Imprime has been studied in combination with PEM, in metastatic TNBC and advanced melanoma in a recently completed Ph2 trial (IMPRIME 1) where in TNBC pts the objective response rate (ORR) = 15.9%, disease control rate (DCR) = 54.5%, median duration of response (mDoR)=12.7mo, median progression free survival (mPFS) =2.86 mo, 12-month overall survival (OS) rate = 57.6%, and median OS= 16.4 months. Clinical benefit in IMPRIME 1 was particularly evident in a subset of pts, mTNBC “converters” (12/44 total TNBC pts) who had originally been diagnosed with ER/PR+ disease and progressed through endocrine therapies +/- CDK4/6 inhibitors. In these 12 TNBC converters, the ORR = 50%, DCR = 83%, mDoR=11.2, mPFS=5.6 mo, 12-month OS rate=64.8%, and mOS= 17.4 months. Imprime is now being explored in pts with hormone-resistant metastatic breast cancer (MBC) in combination with PEM. This is a phase 2, Simon’s 2-Stage study of pts with MBC who have progressed through prior hormonal therapy with at least one CDK4/6 inhibitor. All pts will receive Imprime 4 mg/kg/wk + PEM 200 mg Q3wk. A total of 23 pts will be enrolled into Stage 1. If ≥4 pts in Stage 1 have an objective response after 12 wks of treatment, the study will proceed into Stage 2. Twenty-four (24) pts will be enrolled in Stage 2 for a total combined population of 47 pts. Rejection of the null hypothesis will require documenting at least 10 objective responses in the total population. Main eligibility criteria include a diagnosis of MBC having failed prior hormonal therapy with at least one CDK4/6 inhibitor, ≤1 prior line of chemotherapy, serum ABA level of ≥20 µg/mL, and no prior ICI exposure. The primary endpoint is ORR (per RECIST v1.1); secondary endpoints are mPFS, PFS, mOS, OS, DCR, DoR, and safety. Exploratory objectives will assess the impact of the treatment combination on immune activating events in peripheral blood and at the tumor level, and correlate changes in PD-L1 status, the tumor microenvironment, and serum ABA with response. Point estimates with the exact 95% confidence intervals of ORR and DCR will be computed. For mPFS, PFS, mOS, OS, and DoR, medians, first, and third quartiles with 95% confidence intervals (CIs) will be estimated using Kaplan-Meier method. Safety parameters will be summarized. The trial is sponsored by HiberCell, Inc. in collaboration with Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Approximately 25 US sites will participate in the study. For information, contact Nick Niles nniles@hibercell.com. 612.230.5846. Citation Format: Alison Stopeck, Michele Gargano, Nandita Bose, Nick Niles, Michael Chisamore, Jose Iglesias. A multicenter, open-label, phase 2 study of Imprime PGG and pembrolizumab in patients with metastatic breast cancer who have progressed through prior hormonal therapy [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 OT1-18-05.

INTRODUCTION Neoadjuvant chemotherapy is standard treatment for locally advanced (LABC) or inflammatory breast cancer (IBC). We hypothesized adding sunitinib, a tyrosine kinase inhibitor with anti-tumor and anti-angiogenic activity, to an anthracycline and taxane regimen would improve pathologic complete response (pCR) rates to a prespecified endpoint of 45% in patients with HER2 negative LABC or IBC. PATIENTS AND METHODS We conducted a multicenter, phase II trial of neoadjuvant sunitinib with paclitaxel (S+T) followed by doxorubicin and cyclophosphamide plus G-CSF for patients with HER2 negative LABC or IBC. Patients received sunitinib 25 mg PO daily with paclitaxel 80 mg/m2 IV weekly x12 followed by doxorubicin 24 mg/m2 IV weekly + cyclophosphamide 60 mg/m2 PO daily with G-CSF support. Response was evaluated using pCR in the breast and the Clinical-pathologic scoring + estrogen receptor (ER) and grade (CPS+EG) score. RESULTS Seventy patients enrolled and 66 were evaluable for efficacy. Eighteen patients (27%) had pCR in the breast (10 had ER+ disease and 8 had triple negative disease). When defining response as pCR and/or CPS+EG score ≤ 2, 47% were responders. In ER+ patients, 23 (64%) were responders. The most common toxicities were cytopenias and fatigue. CONCLUSIONS Neoadjuvant S+T followed by AC+G-CSF was safe and tolerable in LABC and IBC. The study did not meet the prespecified endpoint for pCR. However, 47% were responders using pCR and/or CPS+EG score ≤2. ER+ patients had the highest response rate (64%). The addition of sunitinib to neoadjuvant chemotherapy may provide promising incremental benefit for ER+ patients.