Phase II Trial of Cabozantinib in Recurrent/Metastatic Endometrial Cancer: A Study of the Princess Margaret, Chicago, and California Consortia (NCI9322/PHL86).

PURPOSE: The relevance of the MET/hepatocyte growth factor pathway in endometrial cancer tumor biology supports the clinical evaluation of cabozantinib in this disease. PATIENTS AND METHODS: PHL86/NCI#9322 (NCT01935934) is a single arm study that evaluated cabozantinib (60 mg once daily) in women with endometrial cancer with progression after chemotherapy. Coprimary endpoints were response rate and 12-week progression-free-survival (PFS). Patients with uncommon histology endometrial cancer (eg, carcinosarcoma and clear cell) were enrolled in a parallel exploratory cohort. RESULTS: A total of 102 patients were accrued. Among 36 endometrioid histology patients, response rate was 14%, 12-week PFS rate was 67%, and median PFS was 4.8 months. In serous cohort of 34 patients, response rate was 12%, 12-week PFS was 56%, and median PFS was 4.0 months. In a separate cohort of 32 patients with uncommon histology endometrial cancer (including carcinosarcoma), response rate was 6% and 12-week PFS was 47%. Six patients were on treatment for >12 months, including two for >30 months. Common cabozantinib-related toxicities (>30% patients) included hypertension, fatigue, diarrhea, nausea, and hand-foot syndrome. Gastrointestinal fistula/perforation occurred in four of 70 (6%) patients with serous/endometrioid cancer and five of 32 (16%) patients in exploratory cohort. We observed increased frequency of responses with somatic CTNNB1 mutation [four partial responses (PRs) in 10 patients, median PFS 7.6 months] and concurrent KRAS and PTEN/PIK3CA mutations (three PRs in 12 patients, median PFS 5.9 months). CONCLUSIONS: Cabozantinib has activity in serous and endometrioid histology endometrial cancer. These results support further evaluation in genomically characterized patient cohorts.

Adjuvant denosumab in early breast cancer (D-CARE): an international, multicentre, randomised, controlled, phase 3 trial.

BACKGROUND: Denosumab is a fully human monoclonal antibody that binds to, and inhibits, the receptor activator of RANKL (TNFSF11) and might affect breast cancer biology, as shown by preclinical evidence. We aimed to assess whether denosumab combined with standard-of-care adjuvant or neoadjuvant systemic therapy and locoregional treatments would increase bone metastasis-free survival in women with breast cancer. METHOD: In this international, double-blind, randomised, placebo-controlled, phase 3 study (D-CARE), patients were recruited from 389 centres in 39 countries. We enrolled women (aged ≥ 18 years) with histologically confirmed stage II or III breast cancer and an Eastern Cooperative Oncology Group performance status of 0 or 1. On eligibility confirmation, investigators at each site telephoned an interactive voice response system to centrally randomly assign patients (1:1) based on a fixed stratified permuted block randomisation list (block size 4) to receive either denosumab (120 mg) or matching placebo subcutaneously every 3-4 weeks, starting with neoadjuvant or adjuvant chemotherapy, for about 6 months and then every 12 weeks for a total duration of 5 years. Stratification factors were breast cancer therapy, lymph node status, hormone receptor and HER2 status, age, and geographical region. The primary endpoint was the composite endpoint of bone metastasis-free survival. This trial is registered with ClinicalTrials.gov, NCT01077154. FINDINGS: Between June 2, 2010, and Aug 24, 2012, 4509 women were randomly assigned to receive denosumab (n=2256) or placebo (n=2253) and included in the intention-to-treat analysis. The primary analysis of the study was done when all patients had the opportunity to complete 5 years of follow-up with an analysis data cutoff date of Aug 31, 2017. The primary endpoint of bone metastasis-free survival was not significantly different between the groups (median not reached in either group; hazard ratio 0·97, 95% CI 0·82-1·14; p=0·70). The most common grade 3 or worse treatment-emergent adverse events, reported in patients who had at least one dose of the investigational product (2241 patients with denosumab vs 2218 patients with placebo), were neutropenia (340 [15%] vs 328 [15%]), febrile neutropenia (112 [5%] vs 142 [6%]), and leucopenia (62 [3%] vs 61 [3%]). Positively adjudicated osteonecrosis of the jaw occurred in 122 (5%) of 2241 patients treated with denosumab versus four (<1%) of 2218 patients treated with placebo; treatment-emergent hypocalcaemia occurred in 152 (7%) versus 82 (4%). Two treatment-related deaths occurred in the placebo group due to acute myeloid leukaemia and depressed level of consciousness. INTERPRETATION: Despite preclinical evidence suggesting RANKL inhibition might delay bone metastasis or disease recurrence in patients with early-stage breast cancer, in this study, denosumab did not improve disease-related outcomes for women with high-risk early breast cancer. FUNDING: Amgen.

Erratum: Zare, A. et al. RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis. Cancers, 2018, 10, 184.

The authors wish to make the following correction to their paper [...].

A Clinical and Molecular Phase II Trial of Oral ENMD-2076 in Ovarian Clear Cell Carcinoma (OCCC): A Study of the Princess Margaret Phase II Consortium.

PURPOSE: Patients with recurrent ovarian clear cell carcinoma (OCCC) have limited effective options due to chemoresistance. A phase II study was designed to assess the activity of ENMD-2076, an oral multitarget kinase selective against Aurora A and VEGFR. PATIENTS AND METHODS: This multicenter phase II study included patients with recurrent OCCC who received prior platinum-based chemotherapy. Primary endpoints were objective response and 6-month progression-free survival (PFS) rates. Correlative analyses include ARID1A and PTEN expression by IHC and gene sequencing with a targeted custom capture next-generation sequencing panel. RESULTS: Forty patients were enrolled with a median age of 54, of which 38 patients were evaluable. ENMD-2076 was well tolerated with main related grade 3 toxicities being hypertension (28%), proteinuria (10%), and diarrhea (10%). Best response was partial response for 3 patients (1 unconfirmed) and stable disease for 26 patients. The overall 6-month PFS rate was 22% and differed according to ARID1A expression (ARIDIA- vs. ARID1A+; 33% vs. 12%, P = 0.023). PTEN-positive expression was observed in 20 of 36 patients, and there was no correlation with outcome. Median PFS in patients with PI3KCA wild-type versus PI3KCA-mutated group was 5 versus 3.7 months (P = 0.049). Molecular profiling showed variants in PI3KCA (27%), ARID1A (26%), and TP53 (7%). The patient with the longest treatment duration (22 months) was PTEN wild-type, diploid PTEN with putative biallelic inactivation of ARID1A. CONCLUSIONS: Single-agent ENMD-2076 did not meet the preset bar for efficacy. Loss of ARID1A correlated with better PFS on ENMD-2076 and warrants further investigation as a potential predictive biomarker.

RIPK2: New Elements in Modulating Inflammatory Breast Cancer Pathogenesis.

Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer that is associated with significantly high mortality. In spite of advances in IBC diagnoses, the prognosis is still poor compared to non-IBC. Due to the aggressive nature of the disease, we hypothesize that elevated levels of inflammatory mediators may drive tumorigenesis and metastasis in IBC patients. Utilizing IBC cell models and patient tumor samples, we can detect elevated NF-κB activity and hyperactivation of non-canonical drivers of NF-κB (nuclear factor kappaB)-directed inflammation such as tyrosine phosphorylated receptor-interacting protein kinase 2 (pY RIPK2), when compared to non-IBC cells or patients. Interestingly, elevated RIPK2 activity levels were present in a majority of pre-chemotherapy samples from IBC patients at the time of diagnosis to suggest that patients at diagnosis had molecular activation of NF-κB via RIPK2, a phenomenon we define as "molecular inflammation". Surprisingly, chemotherapy did cause a significant increase in RIPK2 activity and thus molecular inflammation suggesting that chemotherapy does not resolve the molecular activation of NF-κB via RIPK2. This would impact on the metastatic potential of IBC cells. Indeed, we can demonstrate that RIPK2 activity correlated with advanced tumor, metastasis, and group stage as well as body mass index (BMI) to indicate that RIPK2 might be a useful prognostic marker for IBC and advanced stage breast cancer.

Association of Ipilimumab With Safety and Antitumor Activity in Women With Metastatic or Recurrent Human Papillomavirus-Related Cervical Carcinoma.

Importance: Based on evidence of human papillomavirus (HPV)-induced immune evasion, immunotherapy may be an attractive strategy in cervical cancer. Ipilimumab is a fully humanized monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 (CTLA-4), which acts to downregulate the T-cell immune response. Objective: To assess the safety and antitumor activity of ipilimumab in recurrent cervical cancer. Design, Setting, and Participants: A multicenter trial was designed for patients with metastatic cervical cancer (squamous cell carcinoma or adenocarcinoma) with measurable disease and progression after at least 1 line of platinum chemotherapy. A run-in safety cohort using ipilimumab, 3 mg/kg, every 21 days for 4 cycles in 6 patients was followed by a phase II cohort of ipilimumab, 10 mg/kg, every 21 days for 4 cycles and then 4 cycles of maintenance therapy every 12 weeks for patients demonstrating radiologic response or stabilization. Immune correlative studies were performed on peripheral blood before and after therapy on archival tissue and fresh tumor obtained prior to registration and 7 days after cycle 2. The study was conducted from December 3, 2012, to September 15, 2014. The data were analyzed from April 2016 to June 2016 and in July 2017. Main Outcomes and Measures: The primary end points were safety and objective response rate. Immune analyses were performed on blood and tumor tissue. Results: A total of 42 women (median age, 49 years; range, 23-78 years) were enrolled (29 [69%] squamous cell cervical cancer and 13 [31%] adenocarcinoma; 37 [93%] of 40 patients with tissue available for analysis had HPV-positive confirmation; there was no archival tissue for 2 women). Grade 3 toxic effects included diarrhea in 4 patients, 3 of whom had colitis. Of 34 patients evaluated for best response (Response Evaluation Criteria in Solid Tumors, version 1.1), 1 patient had partial response and 10 had stable disease. The median progression-free survival and overall survival were 2.5 months (95% CI, 2.1-3.2 months) and 8.5 months (95% CI, 3.6-not reached; 1 patient was still alive), respectively. Intratumoral pretreatment CD3, CD4, CD8, FoxP3, indoleamine 2,3-dioxygenase, and programmed cell death ligand 1 (PD-L1) expression was not predictive of benefit and did not significantly change with treatment. Multicolor flow cytometry on peripheral lymphocytes revealed a treatment-dependent increase of inducible T-cell costimulator, human leukocyte antigen-antigen D related, and PD-1 during initial treatment, which returned to baseline during maintenance. Conclusions and Relevance: Ipilimumab was tolerable in this population but did not show significant single-agent activity. Immune changes were induced by anti-CTLA-4 therapy but did not correlate with clinical activity. Changes in these markers may guide further treatment strategies.

Feasibility Study of an Online Intervention to Support Male Spouses of Women With Breast Cancer.

PURPOSE/OBJECTIVES: To evaluate the feasibility of a web-based psychosocial supportive intervention entitled Male Transition Toolkit (MaTT). 
. DESIGN: Randomized, controlled trial, mixed methods, concurrent feasibility design.
. SETTING: Edmonton, a large metropolitan city in western Canada.
. SAMPLE: 40 dyads (women with breast cancer and their spouse).
. METHODS: Male spouse participants in the treatment group accessed MaTT for four weeks. Data on hope, quality of life, general self-efficacy, and caregiver guilt were collected at baseline and days 14, 28, and 56. Quality-of-life data were collected from the women with breast cancer at each time period. Qualitative data were collected from the usual care group in an open-ended interview and from the treatment group in an evaluation survey on days 14 and 28.
. MAIN RESEARCH VARIABLES: Feasibility, as measured by the MaTT questionnaire. 
. FINDINGS: Evaluation survey scores indicated that MaTT was feasible, acceptable, and easy to use. Male spouse quality-of-life scores were not significantly different between groups. As guilt scores decreased, male spouses' quality of life increased. 
. CONCLUSIONS: The findings provided useful information to strengthen MaTT and improve study design. Additional research is needed to determine its efficacy in improving male spouses' quality of life. 
. IMPLICATIONS FOR NURSING: MaTT is a feasible intervention. Future research should evaluate MaTT with larger samples as well as determine the amount of time participants used MaTT.

'All I can do is help': Transition experiences of male spouse caregivers of women with breast cancer.

The transition experience of male spouses of women with breast cancer is largely unknown. Ninety-one open-ended surveys of male spouses were analyzed using thematic analysis to understand the transition experience of this population when their partners were diagnosed and treated for breast cancer. While 10 participants indicated they experienced no changes, the majority experienced changes to their roles and relationships, their mental health, and their share of household work. Spouses took on a supportive role. They adjusted to the changes they faced by proactively becoming aware of their situation, fostering a positive approach, and being actively involved in their partners' experiences. Implications for nurses entail recognizing the role of the spouse, as well as facilitating access to reliable information and support networks.