Higher serum PD-L1 level predicts increased overall survival with lapatinib versus trastuzumab in the CCTG MA.31 phase 3 trial.

BACKGROUND: The purpose of this retrospective biomarker study of the Canadian Cancer Trials Group (CCTG) MA.31 randomized phase 3 trial (lapatinib vs trastuzumab) of HER2-positive metastatic breast cancer (MBC) was to evaluate the prognostic and predictive biomarker utility of pretreatment serum programmed death ligand 1 (PD-L1) levels. METHODS: CCTG MA.31 accrued 652 HER2-positive patients; 387 had serum available (185 in the trastuzumab arm and 202 in the lapatinib arm). The Ella immunoassay platform (ProteinSimple, San Jose, California) was used to quantitate serum PD-L1 levels. Stepwise forward Cox multivariable analyses were performed for progression-free survival and overall survival (OS). RESULTS: In the whole trial population, continuous pretreatment serum PD-L1 levels were not associated with OS. However, within the trastuzumab arm, a higher continuous pretreatment serum PD-L1 level was significant for shorter OS (hazard ratio [HR], 3.85; P = .04), but within the lapatinib arm, pretreatment serum PD-L1 was not associated with OS (P = .37). In the whole trial, in a multivariable analysis for OS, serum PD-L1 (median cut point) remained a significant independent covariate (HR, 2.38; P = .001). There was a significant interaction between treatment arm and continuous serum PD-L1 (bootstrap method; P = .0025): at or above 214.2 pg/mL (the 89th percentile), serum PD-L1 was associated with significantly shorter OS with trastuzumab treatment versus lapatinib treatment. CONCLUSIONS: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: a higher pretreatment serum PD-L1 level was associated with shorter OS with trastuzumab treatment but with longer OS with lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in advanced breast cancer is warranted to identify patients with HER2-positive MBC who may benefit from novel immune-targeted therapies in addition to trastuzumab.

Interest Among Primary Care Patients in Group Problem-Solving Gameplay for Mental Health.

Mental health programs to improve problem-solving skills and reduce stress through social gameplay can improve psychiatric outcomes, but little is known about whether adult patients are interested in using them. Primary care patients (n = 467) completed a cross-sectional survey to assess interest in using 2 types of group programs for mental health. A significantly greater percentage (23.7%) of patients expressed interest in a gameplay-based program than in interpersonal therapy (17.6%) (P < .001). Lonely patients and younger patients were more likely to report interest in gameplay. Results suggest that diverse patient populations are interested in using gameplay programs for mental health.

Update on clinical trials: genetic targets in breast cancer.

Breast cancer is the most commonly diagnosed cancer in women in United States. From data of American Cancer Society from 2007 reported total of 178,480 women diagnosed with breast cancer. The death rate from breast cancer has decreased in North America over time, but still accounts for second highest cancer death, following lung cancer. Breast cancer is staged based on tumor size, nodal involvement, and distant metastasis like any other solid tumors. However clinical staging is not the only important factor in management of breast cancer. Various molecular features divides breast cancer into many subgroups - that act differently, and respond differently from therapy. Thus the focus of breast cancer treatment has evolved focusing on specific targets. The most important biologic markers in subtyping of breast cancer so far are hormone receptor positivity and HER2/neu protein expression. Five molecular subtypes using intrinsic gene set include Basal mRNA, HER2 + mRNA, Luminal AmRNA, Luminal B mRNA, and Normal-like mRNA. In addition, better understanding of genetic target of breast cancer has given us arsenal of personalized, and more effective treatment approach.This review will focus on examples that highlight several mechanism of tumorigenesis, giving us not just understanding of gene pathways and the molecular biology, that could lead us to therapeutic target. Several important molecular targets have been investigated in preclinical and clinical trials, others are yet to be explored. We will also describe genetic mechanisms discovery related to overcoming resistance to current targeted therapies in breast cancer, including hormone receptor expression and HER 2- neu amplification. We will also review other exciting developments in understanding of breast cancer, the tumor microenvironment and cancer stem cells, and targeting agents in that area.

Feasibility of a tailored home-based exercise intervention during neoadjuvant chemotherapy in breast cancer patients.

PURPOSE: To evaluate the feasibility of a home-based moderate-to-vigorous intensity, phased (introduction, intermediate, maintenance), exercise prescription in breast cancer patients receiving cardiotoxic neoadjuvant chemotherapy. METHODS: Nineteen breast cancer patients were randomized to intervention or control for the duration of chemotherapy (16-24 weeks). The intervention was one aerobic exercise session at 80-90% VO2max for 25 min/week and 65%-75% VO2max for ≥ 50 min/week. Adherence to the tailored home-based program was assessed by heart rate monitors. Acceptability, tolerability, feasibility, efficacy, change in VO2max, and patient reported outcomes, safety, and clinical events were assessed. RESULTS: 25.7% of eligible women consented (acceptability). Adherence was 87.6%. Women were not able to maintain exercise intensity as chemotherapy progressed (23.7% of exercise minutes were completed at prescribed heart rate during maintenance). Efficacy of the intervention was demonstrated by maintenance of VO2max (-1.0 ± 13.2%) compared to (-27.5 ± 7.4%) the control group. Further, during and after therapy, patients in the intervention arm reported less fatigue (control-baseline: 14.4 ± 15.9; midpoint: 19.0 ± 11.4; follow-up: 29.4 ± 20.0; intervention-baseline: 29.2 ± 24.6; midpoint: 24.6 ± 14.4; follow-up: 23.6 ± 11.9), impairment in activities (control-baseline: 13.7 ± 16.0; midpoint: 32.8 ± 17.0; follow-up: 58.6 ± 27.9; intervention-baseline: 38.7 ± 31.8; midpoint: 47.1 ± 27.5; follow-up: 47.5 ± 31.0), and pain (control-baseline: 80.8 ± 17.1; midpoint: 73.9 ± 20.7; follow-up: 50.7 ± 25.7; intervention-baseline: 68.7 ± 28.4; midpoint: 61.4 ± 22.5; follow-up: 65.3 ± 22.4). There were no differences in adverse events, treatment delays, or pathological complete response. CONCLUSIONS: Neoadjuvant breast cancer patients maintained approximately one hour/week of moderate-intensity exercise over the course of their treatment. Further, this volume of exercise was sufficient to maintain fitness capacity and quality of life compared to the control group. TRIAL REGISTRY: ClinicalTrials.gov Identifier: NCT03280836, prospectively registered 9/13/2017, https://clinicaltrials.gov/ct2/show/NCT03280836 .

Testing the acceptability and feasibility of a tablet-based supportive cancer platform for patients with metastatic breast cancer.

BACKGROUND: Although metastatic breast cancer (MBC) survival is improving, symptoms remain a significant burden. Returning to a cancer center for symptom management can be challenging. Technology-enabled supportive care platforms are worth exploration. METHODS: Seventeen patients with MBC were randomized to immediate or delayed start for a 3-month intervention that included daily tablet-based guideline-concordant self-care for pain, distress, fatigue, and sleep disturbance, as well as weekly calls with a patient navigator. The primary outcome was patient acceptability. We also assessed feasibility, patient satisfaction, and cost and compared between group differences for symptoms. RM-ANOVA examined between group differences over time. Hedges' d effect sizes quantified magnitude of differences in change between immediate and delayed start. RESULTS: Sixty-eight percent of patients approached accepted the tablet-based intervention. Patients interacted with the tablet 48% of possible days. Patient satisfaction ranged from 83 for walking to 49% for the psychological interventions. The cost of delivering Nurse AMIE for 3 months was $570.23. Small nonsignificant improvements were found for fatigue (d=0.24). Nonsignificant, but potentially clinically meaningful, moderate reductions were found for sleep (d=0.65) and distress (d=0.74). DISCUSSION: A tablet-based supportive care platform that offers guideline-concordant self-care for pain, fatigue, sleep, and distress was observed to be highly acceptable and feasible for patients with metastatic breast cancer. Patient satisfaction scores and initial evaluation of efficacy are promising, and the platform warrants further investigation. IMPLICATIONS FOR CANCER SURVIVORS: Technology-based self-care is a promising option to address symptoms in patients with metastatic breast cancer.

Doxorubicin, paclitaxel, and cisplatin based chemotherapy for the treatment of angiosarcoma: Two case reports.

INTRODUCTION: Angiosarcoma is a rare soft tissue malignancy of endothelial cells, generally associated with a poor prognosis. Due to its rarity, randomized trials are difficult to conduct and a consensus on the treatment of angiosarcoma has not been reached. The role, efficacy, and timing of chemotherapy in AS treatment remain uncertain, and as stated, no large-scale trials have been able to establish definitive recommendations. CASE DESCRIPTIONS: Here we describe the successful use of chemotherapy followed by radiation for a case of lower extremity angiosarcoma, and a case of breast angiosarcoma treated with neoadjuvant chemotherapy followed by surgical resection. Systemic therapy consisted of weekly doxorubicin, paclitaxel, and cisplatin. This regimen resulted in a full clinical remission in the first patient and a pathologic complete response in the second. DISCUSSION: These cases suggest that the use of the doxorubicin, cisplatin and paclitaxel combination could be an effective alternative to radical surgical excision in extremity sarcomas, and an effective adjuvant treatment to mastectomy in cutaneous radiation-associated angiosarcoma of the breast due to their independent efficacy against angiosarcoma. A randomized trial utilizing neoadjuvant combined doxorubicin, paclitaxel and cisplatin followed by either surgery or radiation, with endpoints assessing pathologic and overall response as well as progression free survival is warranted based on these cases. CONCLUSION: The role of neoadjuvant chemotherapy in the treatment of angiosarcoma should be reconsidered considering its ability to provide important prognostic information and improve the likelihood of curative surgery.

A Novel Adverse Event Associated with Olaparib Therapy in a Patient with Metastatic Breast Cancer.

Olaparib was first FDA approved for use in women with advanced ovarian cancer and germline BRCA mutations. Based on the results of subsequent research, the use of this drug has been expanded to patients with metastatic breast cancer with germline BRCA mutation. With the use of a relatively new medication and a larger patient population eligible for therapy, monitoring for novel adverse events associated with therapy is important. This case represents a patient with metastatic breast cancer and germline BRCA2 mutation who developed erythema nodosum after initiation of therapy with olaparib capsules. Her characteristic rash appeared shortly after starting olaparib and recurred after restarting olaparib an additional two times. She was treated with short courses of prednisone therapy with or without holding olaparib with resolution of her rash. The patient was later restarted on olaparib capsules 200 mg twice daily, and she more recently has been maintained on olaparib tablets 300 mg twice daily. On both regimens, the patient experienced only attenuated episodes of erythema nodosum that have not required cessation of therapy or steroid therapy.

Biology of bone metastases: causes and consequences.

Breast cancer is a highly osteotropic neoplasm, and as many as 75% of patients with metastatic disease will have involvement of the bony skeleton. On radiologic examination, these metastases are predominantly osteolytic but can be osteoblastic or mixed. The mechanisms by which metastases are formed are complex, involving many steps that include angiogenesis, invasion, and proliferation in the bone microenvironment. Tumor cells in the bone microenvironment produce a large number of cytokines that stimulate osteoclastic activity. Increased osteoclastic activity, in turn, leads to production of a variety of lymphokines and growth factors that can increase tumor cell proliferation. Thus, a cytokine network is established, which results in an imbalance of the processes of bone formation and bone resorption. As tumor burden in bone increases, osteoclast-mediated bone resorption is accelerated, resulting in loss of bone strength, fractures, pain, and other morbidities. Tumor cells metastatic to bone can also secrete growth factors, leading to increased osteoblastic activity. Osteoblasts lay down an excess of new bone that is structurally weak. There is considerable crosstalk between osteoclasts, osteoblasts, macrophages, and other cellular elements within the bone environment. The increasing understanding of the biology of bone metastases has opened the door to improved management of this important clinical problem. Current treatment strategies include approaches to reduce tumor burden and developing treatments that directly inhibit osteoclast function. The bisphosphonates are a class of drugs that inhibit osteoclast recruitment and function. Several highly potent bisphosphonates are now available for clinical use and represent an important adjunct in the management of bone metastases from breast cancer, multiple myeloma, and several other types of malignancies. Some newer therapeutic approaches include agents designed to inhibit the osteoclast-osteoblast signaling interactions or alter processes of adhesion and invasion.

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.

Predicting therapy response in live tumor cells isolated with the flexible micro spring array device.

Cells disseminated from primary epithelial tumors into peripheral blood, called circulating tumor cells (CTCs), can be monitored to assess metastases and to provide a surrogate marker of treatment response. Here, we demonstrate how the flexible micro spring array (FMSA) device-a novel microfluidic device that enriches CTCs by two physical parameters: size and deformability-could be used in the rational development of treatment intervention and as a method to study the fundamental biology of CTCs. Cancer cells of different origins were spiked into healthy samples of donor blood to mimic blood samples of metastatic cancer patients. This spiked human blood was filtered using the FMSA device, and the recovered cells were successfully expanded in vitro and in a novel in vivo system. A series of experiments were performed to characterize these cells and to investigate the effect of chemotherapy on the resulting cultures. As few as 20 colon cancer cells in 7.5 mL blood could be isolated with the FMSA device, expanded both in vitro and in vivo and used at 25 cells per well to obtain significant and reliable chemosensitivity data. We also show that isolating a low number of viable patient CTCs and maintaining them in culture for a few weeks is possible. The isolation of viable cancer cells from human blood using the FMSA device provides a novel and realistic means for studying the biology of viable CTCs and for testing drug efficacy on these rare cells-a hypothesis that can be tested in future clinical trials.