Tessa Cigler

EMERGE: A Randomized Phase II Study of the Antibody-Drug Conjugate Glembatumumab Vedotin in Advanced Glycoprotein NMB–Expressing Breast Cancer

PURPOSE Glycoprotein NMB (gpNMB), a negative prognostic marker, is overexpressed in multiple tumor types. Glembatumumab vedotin is a gpNMB-specific monoclonal antibody conjugated to the potent cytotoxin monomethyl auristatin E. This phase II study investigated the activity of glembatumumab vedotin in advanced breast cancer by gpNMB expression. PATIENTS AND METHODS Patients (n = 124) with refractory breast cancer that expressed gpNMB in ≥ 5% of epithelial or stromal cells by central immunohistochemistry were stratified by gpNMB expression (tumor, low stromal intensity, high stromal intensity) and were randomly assigned 2:1 to glembatumumab vedotin (n = 83) or investigators choice (IC) chemotherapy (n = 41). The study was powered to detect overall objective response rate (ORR) in the glembatumumab vedotin arm between 10% (null) and 22.5% (alternative hypothesis) with preplanned investigation of activity by gpNMB distribution and/or intensity (Stratum 1 to Stratum 3). RESULTS Glembatumumab vedotin was well tolerated as compared with IC chemotherapy (less hematologic toxicity; more rash, pruritus, neuropathy, and alopecia). ORR was 6% (five of 83) for glembatumumab vedotin versus 7% (three of 41) for IC, without significant intertreatment differences for predefined strata. Secondary end point revealed ORR of 12% (10 of 83) versus 12% (five of 41) overall, and 30% (seven of 23) versus 9% (one of 11) for gpNMB overexpression (≥ 25% of tumor cells). Unplanned analysis showed ORR of 18% (five of 28) versus 0% (0 of 11) in patients with triple-negative breast cancer (TNBC), and 40% (four of 10) versus 0% (zero of six) in gpNMB-overexpressing TNBC. CONCLUSION Glembatumumab vedotin is well tolerated in heavily pretreated patients with breast cancer. Although the primary end point in advanced gpNMB-expressing breast cancer was not met for all enrolled patients (median tumor gpNMB expression, 5%), activity may be enhanced in patients with gpNMB-overexpressing tumors and/or TNBC. A pivotal phase II trial (METRIC [Metastatic Triple-Negative Breast Cancer]) is underway.

Tetrathiomolybdate-associated copper depletion decreases circulating endothelial progenitor cells in women with breast cancer at high risk of relapse

BACKGROUND Bone marrow-derived endothelial progenitor cells (EPCs) are critical for metastatic progression. This study explores the effect of tetrathiomolybdate (TM), an anti-angiogenic copper chelator, on EPCs in patients at high risk for breast cancer recurrence. PATIENTS AND METHODS This phase 2 study enrolled breast cancer patients with stage 3 and stage 4 without evidence of disease (NED), and stage 2 if triple-negative. TM 100 mg orally was administered to maintain ceruloplasmin <17 mg/dl for 2 years or until relapse. The primary end point was change in EPCs. RESULTS Forty patients (28 stage 2/3, 12 stage 4 NED) were enrolled. Seventy-five percent patients achieved the copper depletion target by 1 month. Ninety-one percent of triple-negative patients copper-depleted compared with 41% luminal subtypes. In copper-depleted patients only, there was a significant reduction in EPCs/ml by 27 (P = 0.04). Six patients relapsed while on study, of which only one patient had EPCs maintained below baseline. The 10-month relapse-free survival was 85.0% (95% CI 74.6%-96.8%). Only grade 3/4 toxicity was hematologic: neutropenia (3.1% of cycles), febrile neutropenia (0.2%), and anemia (0.2%). CONCLUSIONS TM is safe and appears to maintain EPCs below baseline in copper-depleted patients. TM may promote tumor dormancy and ultimately prevent relapse.

Association Between Use of a Scalp Cooling Device and Alopecia After Chemotherapy for Breast Cancer

Importance Chemotherapy-induced alopecia is a common and distressing adverse effect. In previous studies of scalp cooling to prevent chemotherapy-induced alopecia, conclusions have been limited. Objectives To evaluate whether use of a scalp cooling system is associated with a lower amount of hair loss among women receiving specific chemotherapy regimens for early-stage breast cancer and to assess related changes in quality of life. Design, Setting, and Participants A prospective cohort study conducted at 5 US medical centers of women with stage I or II breast cancer receiving adjuvant or neoadjuvant chemotherapy regimens excluding sequential or combination anthracycline and taxane (106 patients in the scalp cooling group and 16 in the control group; 14 matched by both age and chemotherapy regimen). The study was conducted between August 2013 and October 2014 with ongoing annual follow-up for 5 years. Exposures Use of a scalp cooling system. Scalp cooling was initiated 30 minutes prior to each chemotherapy cycle, with scalp temperature maintained at 3°C (37°F) throughout chemotherapy and for 90 minutes to 120 minutes afterward. Main Outcomes and Measures Self-estimated hair loss using the Dean scale was assessed 4 weeks after the last dose of chemotherapy by unblinded patient review of 5 photographs. A Dean scale score of 0 to 2 (⩽50% hair loss) was defined as treatment success. A positive association between scalp cooling and reduced risk of hair loss would be demonstrated if 50% or more of patients in the scalp cooling group achieved treatment success, with the lower bound of the 95% CI greater than 40% of the success proportion. Quality of life was assessed at baseline, at the start of the last chemotherapy cycle, and 1 month later. Median follow-up was 29.5 months. Results Among the 122 patients in the study, the mean age was 53 years (range, 28-77 years); 77.0% were white, 9.0% were black, and 10.7% were Asian; and the mean duration of chemotherapy was 2.3 months (median, 2.1 months). No participants in the scalp cooling group received anthracyclines. Hair loss of 50% or less (Dean score of 0-2) was seen in 67 of 101 patients (66.3%; 95% CI, 56.2%-75.4%) evaluable for alopecia in the scalp cooling group vs 0 of 16 patients (0%) in the control group (P < .001). Three of 5 quality-of-life measures were significantly better 1 month after the end of chemotherapy in the scalp cooling group. Of patients who underwent scalp cooling, 27.3% (95% CI, 18.0%-36.6%) reported feeling less physically attractive compared with 56.3% (95% CI, 31.9%-80.6%) of patients in the control group (P = .02). Of the 106 patients in the scalp cooling group, 4 (3.8%) experienced the adverse event of mild headache and 3 (2.8%) discontinued scalp cooling due to feeling cold. Conclusions and Relevance Among women undergoing non–anthracycline-based adjuvant chemotherapy for early-stage breast cancer, the use of scalp cooling vs no scalp cooling was associated with less hair loss at 4 weeks after the last dose of chemotherapy. Further research is needed to assess outcomes after patients receive anthracycline regimens, longer-term measures of alopecia, and adverse effects. Trial Registration clinicaltrials.gov Identifier: NCT01831024

A New Paradigm for Mechanobiological Mechanisms in Tumor Metastasis

Tumor metastases and epithelial to mesenchymal transition (EMT) involve tumor cell invasion and migration through the dense collagen-rich extracellular matrix surrounding the tumor. Little is neither known about the mechanobiological mechanisms involved in this process, nor the role of the mechanical forces generated by the cells in their effort to invade and migrate through the stroma. In this paper we propose a new fundamental mechanobiological mechanism involved in cancer growth and metastasis, which can be both protective or destructive depending on the magnitude of the forces generated by the cells. This new mechanobiological mechanism directly challenges current paradigms that are focused mainly on biological and biochemical mechanisms associated with tumor metastasis. Our new mechanobiological mechanism describes how tumor expansion generates mechanical forces within the stroma to not only resist tumor expansion but also inhibit or enhance tumor invasion by, respectively, inhibiting or enhancing matrix metalloproteinase (MMP) degradation of the tensed interstitial collagen. While this mechanobiological mechanism has not been previously applied to the study of tumor metastasis and EMT, it may have the potential to broaden our understanding of the tumor invasive process and assist in developing new strategies for preventing or treating cancer metastasis.

Eribulin mesylate for the treatment of breast cancer

Importance of the field: Breast cancer is the most common cause of cancer-related death among women in the USA, and additional effective and well-tolerated chemotherapeutic agents are urgently needed. Eribulin mesylate (E7389), a synthetic analog of the marine macrolide halichondrin B, is a microtubule inhibitor with a unique tubulin binding site and mechanism of action. Areas covered in this review: Based on a review of the literature between 2005 and 2010, we present a summary of eribulin and its clinical activity, specifically in metastatic breast cancer. What the reader will gain: The mechanism of action of eribulin, preclinical data indicating antitumor activity of eribulin and data from Phase I and II clinical trials evaluating the efficacy and tolerability of eribulin are presented. Take home message: Based on data from Phase I and II clinical trials, we conclude that eribulin seems to have efficacy in metastatic breast cancer, even among women with heavily pretreated and taxane-resistant disease. In addition, eribulin has a manageable side-effect profile, consisting mainly of neutropenia and fatigue, and most notably a low incidence of peripheral neuropathy. With these encouraging results, additional Phase II and III studies are ongoing. Eribulin seems to be a promising new agent for the treatment of metastatic breast cancer.

Efficacy of the PARP inhibitor veliparib with carboplatin or as a single agent in patients with germline BRCA1- or BRCA2-associated metastatic breast cancer: California Cancer Consortium trial NCT01149083

Purpose: We aimed to establish the MTD of the poly (ADP-ribose) (PAR) polymerase inhibitor, veliparib, in combination with carboplatin in germline BRCA1- and BRCA2- (BRCA)-associated metastatic breast cancer (MBC), to assess the efficacy of single-agent veliparib, and of the combination treatment after progression, and to correlate PAR levels with clinical outcome. Experimental Design: Phase I patients received carboplatin (AUC of 5–6, every 21 days), with escalating doses (50-20 mg) of oral twice-daily (BID) veliparib. In a companion phase II trial, patients received single-agent veliparib (400 mg BID), and upon progression, received the combination at MTD. Peripheral blood mononuclear cell PAR and serum veliparib levels were assessed and correlated with outcome. Results: Twenty-seven phase I trial patients were evaluable. Dose-limiting toxicities were nausea, dehydration, and thrombocytopenia [MTD: veliparib 150 mg po BID and carboplatin (AUC of 5)]. Response rate (RR) was 56%; 3 patients remain in complete response (CR) beyond 3 years. Progression-free survival (PFS) and overall survival (OS) were 8.7 and 18.8 months. The PFS and OS were 5.2 and 14.5 months in the 44 patients in the phase II trial, with a 14% RR in BRCA1 (n = 22) and 36% in BRCA2 (n = 22). One of 30 patients responded to the combination therapy after progression on veliparib. Higher baseline PAR was associated with clinical benefit. Conclusions: Safety and efficacy are encouraging with veliparib alone and in combination with carboplatin in BRCA-associated MBC. Lasting CRs were observed when the combination was administered first in the phase I trial. Further investigation of PAR level association with clinical outcomes is warranted. Clin Cancer Res; 23(15); 4066–76. ©2017 AACR.

Eribulin mesylate in the treatment of metastatic breast cancer

The treatment of metastatic breast cancer (MBC) has become increasingly challenging as the primary goals of therapy include prolonging life without added toxicity. While multiple agents are approved for the therapy of MBC, there is no standard approach for therapy beyond the second-line. Eribulin mesylate, an analog of the marine sponge halichondrin B, is a non-taxane microtubule dynamics inhibitor with a mechanism of action distinct from other tubulin-targeted drugs. Based on a significant extension in overall survival seen in a Phase III clinical trial, eribulin was approved for third-line therapy in MBC patients following anthracycline and taxane failure. Eribulin has a manageable toxicity profile and a low incidence of peripheral neuropathy. In this review, we discuss the natural source of eribulin, pharmacology, mode of action, preclinical and clinical data, and patient-focused perspectives.

Defining the aromatase inhibitor musculoskeletal syndrome: A prospective study

To define the musculoskeletal syndrome associated with use of aromatase inhibitors (AIs), specifically, to describe its incidence, time to onset, risk factors, and clinical presentation.

Ixabepilone-induced mitochondria and sensory axon loss in breast cancer patients.

We sought to define the clinical and ultrastructure effects of ixabepilone (Ix), a microtubule‐stabilizing chemotherapy agent on cutaneous sensory nerves and to investigate a potential mitochondrial toxicity mechanism.

Breast cancer adjuvant endocrine therapy.

Adjuvant endocrine therapy with the selective estrogen receptor modulator, tamoxifen, has significantly improved mortality from early-stage breast cancer for both pre- and postmenopausal women with hormone receptor–positive breast cancer. Recent large clinical trials have demonstrated a clear and consistent benefit for the incorporation of aromatase inhibitor (AI) therapy within adjuvant endocrine regimens for postmenopausal women. The AIs, which are associated with myalgias, arthralgias, and a reduction in bone mineral density, are generally well tolerated and have lower risks of endometrial carcinoma and thromboembolic events than tamoxifen. Data are awaited from ongoing trials to better define the optimal sequencing strategy, duration, and AI agent. Attempts to further optimize adjuvant endocrine therapy by identifying predictive biomarkers of response, as well as by developing strategies to overcome endocrine resistance are underway. In premenopausal women AI monotherapy is currently contraindicated and tamoxifen remains the standard of care. The role of ovarian function suppression in addition to tamoxifen or combined with AI therapy is being explored. The hope is that continued advances in endocrine therapy will translate into improved survival among both pre- and postmenopausal women with receptor-positive breast cancer.