Measuring Ovarian Escape in Premenopausal Estrogen Receptor-Positive Breast Cancer Patients on Ovarian Suppression Therapy.

PURPOSE: This study evaluated the proportion of premenopausal women who experience persistent ovarian escape (OE) while receiving ovarian suppression (OS) therapy for estrogen receptor-positive (ER+) breast cancer treatment. The study also examined clinical factors that may predispose to higher risk of persistent OE. MATERIALS AND METHODS: This was a retrospective, "real-world" study to evaluate premenopausal women receiving adjuvant endocrine OS therapy. The primary objective was to measure the percentage of persistent OE within the first 3 months of OS injections (using either leuprolide or goserelin). The secondary objective was to associate baseline clinical data (age, body mass index [BMI], and previous chemotherapy) with the probability of OE. RESULTS: Of the 46 patients included in this analysis, 11 (23.9%) women did not achieve OS within 3 months. Three women (6.5%) remained in OE at 12 months. Older age (odds ratio, 0.86; confidence interval, 0.76-0.98, p = .024) was associated with lower chance of developing OE. BMI, previous chemotherapy, and drug used (tamoxifen versus aromatase inhibitor) did not correlate with the likelihood of OE in this patient cohort. CONCLUSION: Among the premenopausal women who did not attain complete ovarian suppression, young age was a significant risk factor for likelihood of OE. Although the clinical relevance of this finding is not yet known, it should prompt further studies to determine whether inadequate OS is associated with higher recurrence risk for patients with ER+ breast cancer. IMPLICATIONS FOR PRACTICE: Because up to a quarter of premenopausal women do not attain adequate ovarian suppression within the first 3 months of gonadotropin-releasing hormone (GnRH) agonist therapy, bloodwork should be checked to ascertain hormone levels prior to starting aromatase inhibitor therapy, and at regular intervals, for these women.

ANETT: PhAse II trial of NEoadjuvant TAK-228 plus Tamoxifen in patients with hormone receptor-positive breast cancer.

INTRODUCTION: Neoadjuvant endocrine therapy is often utilized to downstage Estrogen Receptor-positive (ER+) breast cancer prior to surgery. However, this approach is sometimes met with endocrine resistance mechanisms within the tumor. This trial examines the safety and efficacy of tamoxifen in combination with an mTORC1/2 inhibitor, TAK-228, in the neoadjuvant treatment of ER+ breast cancer. METHODS: In this single-arm, open-label trial, pre- and post-menopausal women were enrolled to receive neoadjuvant tamoxifen (20 mg daily) with TAK-228 (30 mg weekly) for 16 weeks prior to surgery. Patient had tissue sampling at baseline, week 6, and week 16. The primary endpoint was change in Ki-67 from baseline to 6 weeks. The toxicity, change in tumor size, pathologic complete response rate, PEPI score, and baseline Oncotype Dx score were also assessed. RESULTS: Twenty-eight women were enrolled on the trial, and 25 completed the entire study course. The combination of tamoxifen and TAK-228 resulted in a significant reduction in Ki-67 from 18.3 to 15.2% (p = 0.0023). The drug was also found to be safe and tolerable. While nausea and hyperglycemia were common side effects, these were manageable. The tumor size also significantly decreased with the treatment, with a median decrease of 0.75 cm (p < 0.0001). There were no pathologic complete responses. CONCLUSION: Tamoxifen and TAK-228 was safe and well tolerated neoadjuvant treatment for ER+ breast cancer, preliminary evidence of activity with significant reduction in both Ki-67 and tumor size, warranting further evaluation in a larger study.

Relationship between clinical features, GEP class, and PRAME expression in uveal melanoma.

BACKGROUND: Metastatic risk for uveal melanoma (UM) patients can be characterized by gene expression profiling (GEP) (Castle Biosciences, Friendswood, TX). Class 1A tumors carry low metastatic risk; class 1B tumors have intermediate risk; and class 2 tumors have high risk. Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated antigen which is expressed in various neoplasms including UM. Recently, PRAME expression in uveal melanoma was first recognized to confer an additional metastatic risk beyond GEP status. METHODS: This was a retrospective, consecutive, multicenter chart review study. All patients diagnosed with UM at two major ocular oncology centers from August 2016 to February 2018 who underwent both GEP and PRAME mRNA expression testing were included. Patient age at diagnosis, gender, and tumor variables such as thickness, largest basal diameter (LBD), tumor volume, TNM stage, and GEP class and PRAME status were extracted from the medical records. Statistical analysis was performed to analyze the association of PRAME +/- status with all clinical and molecular variables. RESULTS: One hundred forty-eight UM patients were identified. TNM was stage I in 51 (34.5%), stage IIA in 33 (22.3%), stage IIB in 34 (23%), stage IIIA in 20 (13.5%), and stage IIIB in 10 (6.8%) patients. Fifty-five patients (37%) were PRAME-positive, a significant fraction. There was no association between higher TNM stage and positive PRAME status (p = 0.129). PRAME expression was found to be independent of gender, patient age, and tumor thickness. PRAME expression was statistically associated with LBD and tumor volume. Higher GEP class was associated with higher TNM staging (p < 0.001). Worsening GEP class was associated with PRAME+ status with 28% of GEP class 1A tumors having PRAME+ status, 29% of GEP class 1B tumors having PRAME+ status, and 56% of GEP class 2 tumors having PRAME+ status. CONCLUSIONS: In this study cohort, PRAME+ status was significantly associated with LBD and tumor volume as well as worsening GEP class. Nearly a third of GEP class 1A tumors expressed PRAME. Given the recent published data on increased metastatic risk among patients with tumors expressing PRAME, this study suggests that a significant fraction of 1A patients may harbor an increased metastatic risk. Future large, multicenter studies with long-term follow-up will clarify this finding.

Ex vivo expansion of human mobilized peripheral blood stem cells using epigenetic modifiers.

BACKGROUND: Epigenetic modifications likely control the fate of hematopoietic stem cells (HSCs). The chromatin-modifying agents (CMAs), 5-aza-2'-deoxycytidine (5azaD) and trichostatin A (TSA), have previously been shown to expand HSCs from cord blood and marrow. Here we assessed whether CMA can also expand HSCs present in growth factor-mobilized human peripheral blood (MPB). STUDY DESIGN AND METHODS: 5azaD and TSA were sequentially added to CD34+ MPB cells in the presence of cytokines, and the cells were cultured for 9 days. RESULTS: After culture, a 3.6 ± 0.5-fold expansion of CD34+CD90+ cells, a 10.1 ± 0.5-fold expansion of primitive colony-forming unit (CFU)-mix, and a 2.2 ± 0.5-fold expansion of long-term cobblestone-area-forming cells (CAFCs) was observed in 5azaD/TSA-expanded cells. By contrast, cells cultured in cytokines without 5azaD/TSA displayed no expansion; rather, a reduction in CD34+CD90+ cells (0.7 ± 0.1-fold) and CAFCs (0.3 ± 0.1-fold) from their initial numbers was observed. Global hypomethylation corresponding with increased transcript levels of several genes implicated in HSC self-renewal, including HOXB4, GATA2, and EZH2, was observed in 5azaD/TSA-expanded MPB cells in contrast to controls. 5azaD/TSA-expanded MPB cells retained in vivo hematopoietic engraftment capacity. CONCLUSION: MPB CD34+ cells from donors can be expanded using 5azaD/TSA, and these expanded cells retain in vivo hematopoietic reconstitution capacity. This strategy may prove to be potentially useful to augment HSC numbers for patients who fail to mobilize.

The effect of renin-angiotensin-system inhibition on survival and recurrence of N3+ breast cancer patients.

PURPOSE: The purpose of this study was to evaluate the association between the rennin-angiotensin system (RAS) inhibition and the risk of breast cancer (BC) recurrence and progression in N3 positive patients. METHODS: The medical records of patients treated for N3 positive BC in Hacettepe Cancer Institute between 2005 and 2012 were evaluated. Angiotensin converting enzyme (ACE) inhibitors/angiotensin receptor blockers (ARB) users were defined as patients who took these medications for at least 6 months in no evidence of disease (NED) stage after the initial diagnosis. The primary and secondary outcome was disease-free survival (DFS) and overall survival (OS). Kaplan-Meier and Cox proportional hazard models were used. RESULTS: A total of 218 pathologic N3 BC patients were included. Follow up ranged from 12 to 212 months (median 49.58). Thirty one patients used ACE inhibitors/ARBs. Univariate analysis showed BC recurrence was lower and OS was higher among patients who used ACE inhibitors/ ARBs, however without reaching statistical significance (p=0.38 and p=0.24, respectively). RAS inhibition was associated with reduced risk of pathologic N3 BC recurrence. CONCLUSION: To the best of our knowledge this is the second study showing that the use of ACE inhibitors/ARBs may be effective in N3 BC. Because of the limited therapeutic options in BC, new drugs or new therapeutic modalities should be considered. In the future, studies with long-term follow-up may be helpful for their implication in clinical practice.

Preclinical IV busulfan dose-finding study to induce reversible myeloablation in a non-human primate model.

In this study we utilized a large animal model to identify a dose of intravenous busulfan that can cause reversible myelosuppression. Nine baboons (Papio anubis) were treated with IV busulfan at 6.4 (Group A), 8 (Group B), or 9.6 mg/kg (Group C). Peripheral blood counts were measured up to 90 days after treatment and serial bone marrow samples were obtained to analyze CD34+ cell content and colony forming units. Overall, the highest grade of peripheral blood cytopenia was observed 15 days after treatment in all three groups (n = 3/group). In particular, we observed a notable reduction of neutrophil and platelet counts in the blood and the number of marrow CD34+ cells and colony forming units. In contrast, the effect of busulfan on hemoglobin levels was mild. Baboons who received the highest dose of busulfan showed only a 25-35% recovery of marrow CD34+ cells and colony forming units after 90 days of busulfan administration. However, all three groups of animals showed a full recovery of peripheral blood counts and normal marrow cellularity and tri-lineage hematopoiesis after treatment. Notably, all three doses of busulfan were tolerated well without significant extra-medullary toxicity. These results validate the hierarchy of blood cells likely targeted by busulfan, and based on these findings, clinical trials using myelotoxic but not myeloablative doses of intravenous busulfan will be designed for patients with myeloid malignancies.

Outcomes of locally advanced breast cancer patients with ≥ 10 positive axillary lymph nodes.

Breast cancers with 10 or more positive lymph nodes at the time of diagnosis are staged as pathological N3a (pN3a) and they have poor prognosis. Recent studies showed five-year disease-free survival (DFS) and overall survival (OS) rates of N3a disease as 43-66 and 58-81 %, respectively. We herein present outcomes of our patients with stage pN3a breast cancer. Among 2,578 patients diagnosed with invasive breast carcinoma at Hacettepe University Hospital between 2002 and 2012, 218 patients (8.4 %) had pN3a disease and were included and analyzed retrospectively in this study. Patients with internal mammary, infraclavicular, and supraclavicular node metastasis or distant metastasis at initial diagnosis were excluded. Demographic features, tumor characteristics, treatment regimens, and patient outcomes in terms of DFS and OS were analyzed. Lymph node ratio was defined as the ratio of positive to total removed lymph nodes. The median age was 49. Most common histological subtype was ductal carcinoma (82.1 %). About 82.6 % of patients had stage T2/T3 cancers and 47.7 % (104) had grade III cancers. Estrogen and progesterone receptors were positive in 133 (61 %) and 121 (55.5 %) patients, respectively. HER2 status was known for 213 patients and was positive in 87 (39.9 %) patients. A total of 27 (12.6 %) patients had triple-negative tumors. Lymphovascular invasion, extracapsular extension, and perineural invasion were present in 106 (48.6 %), 105 (48.2 %), 20 (9.2 %) cases, respectively. A total of 18 patients (8.3 %) received neoadjuvant and 200 patients (91.7 %) received adjuvant chemotherapy, mostly with anthracycline- (95 %) and taxane (60 %)-containing regimens. A total of 210 patients (96.3 %) received radiotherapy. Median follow-up was 39.5 months. A total of 96 patients relapsed on follow-up and 64 patients died. Nineteen of the relapses were locoregional and 77 were distant relapses. The 5-year DFS rate was 46.2 % and the OS rate was 69.8 %. In multivariate Cox regression analysis, grade III disease (HR 1.899, 95 % CI 1.196-3.017, P = 0.007), perineural invasion (HR 2.519, 95 % CI 1.341-4.731, P = 0.004), and lymph node ratio (≥ 0.9 vs. <0.9) (HR 2.290, 95 % CI 1.368-3.835, P = 0.002) were significantly associated with DFS, and grade III disease (HR 2.679, 95 % CI 1.500-4.782, P = 0.001) and lymph node ratio (≥ 0.9 vs. <0.9) (HR 2.182, 95 % CI 1.211-3.932, P = 0.009) were significantly associated with OS. Patients with pN3a disease in our cohort have comparable survival rates with other reports in the literature. Within this high risk group of patients, those with grade III disease, perineural invasion, and lymph node ratio ≥ 0.9 seem to confer poorer prognosis.