Triple-negative breast cancer is not a contraindication for breast conservation.

BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype shown to have a high risk of locoregional recurrence (LRR). The purpose of this study was to determine the impact of operation type on LRR in TNBC patients. METHODS: A total of 1325 patients with TNBC who underwent breast-conserving therapy (BCT) or mastectomy from 1980 to the present were identified. Clinical and pathological factors were compared by the chi-square test. LRR-free survival (LRRFS), distant metastasis-free survival, and overall survival were estimated by the Kaplan-Meier method. Multivariate analysis was performed by the Cox proportional hazard models. RESULTS: BCT was performed in 651 patients (49%) and mastectomy in 674 (51%). The mastectomy group had larger tumors, a higher incidence of lymphovascular invasion, and higher pathologic N stage (all P < 0.001). At 62-month median follow-up, LRR was seen in 170 (26%) in the BCT group and 203 (30%) in the mastectomy group. Five-year LRRFS rates were higher in the BCT group (76% vs. 71%, P = 0.032), as was distant metastasis-free survival (68% vs. 54%, P < 0.0001) and overall survival (74% vs. 63%, P < 0.0001). On multivariate analysis, T stage (hazard ratio [HR] 1.37, P = 0.006), high nuclear grade (HR 1.92, P = 0.002), lymphovascular invasion (HR 1.93, P < 0.0001), close/positive margins (HR 1.89, P < 0.0001), and use of non-anthracycline or taxane-based adjuvant chemotherapy (HR 2.01, P < 0.0001) increased the LRR risk, while age >50 years was protective (HR 0.73, P = 0.007). Operation type (mastectomy vs. BCT, HR 1.07, P = 0.55) was not statistically significant. CONCLUSIONS: BCT is not associated with increased LRR rates compared to mastectomy. TNBC should not be considered a contraindication for breast conservation.

Triple-negative breast cancer and obesity in a rural Appalachian population.

BACKGROUND: Our objective was to determine the clinicopathologic features of triple-negative (estrogen receptor, progesterone receptor, and human epidermal growth factor-2 receptor negative) breast cancer and their relationship to obesity in women drawn from a population with one of the highest obesity rates in the United States. METHODS: This retrospective study involved 620 White patients with invasive breast cancer in West Virginia. Hospital tumor registry, charts, and pathology records provided age at diagnosis, tumor histologic type, size, nodal status, and receptor status. Body mass index was calculated and a value of > or = 30 was considered indicative of obesity. RESULTS: Triple-negative tumors occurred in 117 (18.9%) of the 620 patients, most often in association with invasive ductal carcinomas. Patients with triple-negative tumors were younger than those with other receptor types, 44.5% and 26.7%, respectively, being diagnosed at age <50 years (P = 0.0004). The triple-negative tumors were larger (P = 0.0003), most notably in the younger women, but small tumors (<2.0 cm) were more often accompanied by lymph node metastases. Obesity was present in 49.6% of those with triple-negative tumors but in only 35.8% of those with non-triple-negative tumors (P = 0.0098). Lymph node metastases were more frequently associated with T(2) tumors in obese patients (P = 0.032) regardless of their receptor status. CONCLUSIONS: Triple-negative breast cancers within a White, socioeconomically deprived, population occurred in younger women, with later stage at diagnosis, and in association with obesity, which itself has been associated with a poor prognosis in breast cancer.

Opioid prescribing practices during implementation of an enhanced recovery program at a tertiary care hospital.

BACKGROUND: Enhanced recovery programs have demonstrated a decrease in opioid use in hospitals where patients have undergone colorectal surgery. This study is to investigate whether similar decreases in opioid prescribing are achieved at discharge and postdischarge. METHODS: Patients undergoing colorectal surgery November 2014-November 2016 were reviewed. Postdischarge opioid prescribing was quantified in morphine milligram equivalents at time of discharge, 30 days postdischarge, and 60 days postdischarge. Linear regression models were used to examine factors predictive of opioid prescribing. RESULTS: A total of 324 patients treated on enhanced recovery program protocol and 451 patients off enhanced recovery program protocol were reviewed. Enhanced recovery program patients had shorter lengths of stay: 6.74 ± 5.3 vs 9.0 ± 7.0 days (mean ± standard deviation; P < .0001). At discharge, enhanced recovery program patients were prescribed higher amounts of opioids (morphine milligram equivalent 307.4 ± 286.3 vs 242.5 ± 243.1 [mean ± SD]; P = .001) and were more likely to receive additional opioid prescriptions in the next 30 days (28.7% vs 18.85%; P = .0013). Linear regression models suggest that preoperative opioid use, age, and treatment on enhanced recovery program protocol were predictive of opioid prescribing (morphine milligram equivalent) at time of discharge. CONCLUSION: Enhanced recovery program patients received more opioid prescribing (morphine milligram equivalent) at discharge and within the first 30 days postdischarge. Alternative confounding variables require further investigation.

Small Bowel Obstruction.

Identifying patients with small bowel obstruction who need operative intervention and those who will fail nonoperative management is a challenge. Without indications for urgent intervention, a computed tomography scan with/without intravenous contrast should be obtained to identify location, grade, and etiology of the obstruction. Most small bowel obstructions resolve with nonoperative management. Open and laparoscopic operative management are acceptable approaches. Malnutrition needs to be identified early and managed, especially if the patient is to undergo operative management. Confounding conditions include age greater than 65, post Roux-en-Y gastric bypass, inflammatory bowel disease, malignancy, virgin abdomen, pregnancy, hernia, and early postoperative state.

Epithelial to mesenchymal transition is associated with rapamycin resistance.

Rapamycin analogues have antitumor efficacy in several tumor types, however few patients demonstrate tumor regression. Thus, there is a pressing need for markers of intrinsic response/resistance and rational combination therapies. We hypothesized that epithelial-to-mesenchymal transition (EMT) confers rapamycin resistance. We found that the epithelial marker E-cadherin protein is higher in rapamycin sensitive (RS) cells and mesenchymal breast cancer cell lines selected by transcriptional EMT signatures are less sensitive to rapamycin. MCF7 cells, transfected with constitutively active mutant Snail, had increased rapamycin resistance (RR) compared to cells transfected with wild-type Snail. Conversely, we transfected two RR mesenchymal cell lines-ACHN and MDA-MB-231-with miR-200b/c or ZEB1 siRNA to promote mesenchymal-to-epithelial transition. This induced E-cadherin expression in both cell lines, and ACHN demonstrated a significant increase in RS. Treatment of ACHN and MDA-MB-231 with trametinib modulated EMT in ACHN cells in vitro. Treatment of MDA-MB-231 and ACHN xenografts with trametinib in combination with rapamycin resulted in significant growth inhibition in both but without an apparent effect on EMT. Future studies are needed to determine whether EMT status is predictive of sensitivity to rapalogs and to determine whether combination therapy with EMT modulating agents can enhance antitumor effects of PI3K/mTOR inhibitors.

In vitro effects of pentosan polysulfate against malignant breast cells.

BACKGROUND: Pentosan polysulfate (Elmiron); (Alza Pharmaceuticals, Mountain View, CA) is the only Food and Drug Administration-approved oral therapy for interstitial cystitis (IC). Women with IC and breast cancer are often in the same age range; therefore, we hypothesize that pentosan polysulfate may also have a therapeutic effect on breast cancer cells in vitro. METHODS: Breast cancer lines MCF-7, ZR75-1, and HTB26 were treated with pentosan polysulfate at various concentrations. Cell viability was measured at 24 hours by MTT. Annexin V assay was used to determine the effect of pentosan polysulfate on apoptotic and necrotic activity. RESULTS: Pentosan polysulfate significantly inhibited the growth of the ZR75-1 cells; however, significant cellular proliferation was observed in the MCF-7 cells. A significant change in late apoptotic activity was observed with pentosan polysulfate treatment in vitro. CONCLUSIONS: Caution should be used in prescribing pentosan polysulfate for the treatment of IC in patients who are both in high-risk groups for breast cancer and premenopausal females.

Catalytic mTOR inhibitors can overcome intrinsic and acquired resistance to allosteric mTOR inhibitors.

We tested the antitumor efficacy of mTOR catalytic site inhibitor MLN0128 in models with intrinsic or acquired rapamycin-resistance. Cell lines that were intrinsically rapamycin-resistant as well as those that were intrinsically rapamycin-sensitive were sensitive to MLN0128 in vitro. MLN0128 inhibited both mTORC1 and mTORC2 signaling, with more robust inhibition of downstream 4E-BP1 phosphorylation and cap-dependent translation compared to rapamycin in vitro. Rapamycin-sensitive BT474 cell line acquired rapamycin resistance (BT474 RR) with prolonged rapamycin treatment in vitro. This cell line acquired an mTOR mutation (S2035F) in the FKBP12-rapamycin binding domain; mTORC1 signaling was not inhibited by rapalogs but was inhibited by MLN0128. In BT474 RR cells, MLN0128 had significantly higher growth inhibition compared to rapamycin in vitro and in vivo. Our results demonstrate that MLN0128 may be effective in tumors with intrinsic as well as acquired rapalog resistance. mTOR mutations are a mechanism of acquired resistance in vitro; the clinical relevance of this observation needs to be further evaluated.

PIK3CA/PTEN mutations and Akt activation as markers of sensitivity to allosteric mTOR inhibitors.

PURPOSE: We sought to determine whether phosphoinositide 3-kinase (PI3K) pathway mutation or activation state and rapamycin-induced feedback loop activation of Akt is associated with rapamycin sensitivity or resistance. EXPERIMENTAL DESIGN: Cancer cell lines were tested for rapamycin sensitivity, Akt phosphorylation, and mTOR target inhibition. Mice injected with breast or neuroendocrine cancer cells and patients with neuroendocrine tumor (NET) were treated with rapalogs and Akt phosphorylation was assessed. RESULTS: Thirty-one cell lines were rapamycin sensitive (RS) and 12 were relatively rapamycin resistant (RR; IC(50) > 100 nmol/L). Cells with PIK3CA and/or PTEN mutations were more likely to be RS (P = 0.0123). Akt phosphorylation (S473 and T308) was significantly higher in RS cells (P < 0.0001). Rapamycin led to a significantly greater pathway inhibition and greater increase in p-Akt T308 (P < 0.0001) and p-Akt S473 (P = 0.0009) in RS cells. Rapamycin and everolimus significantly increased Akt phosphorylation but inhibited growth in an in vivo NET model (BON). In patients with NETs treated with everolimus and octreotide, progression-free survival correlated with p-Akt T308 in pretreatment (R = 0.4762, P = 0.0533) and on-treatment tumor biopsies (R = 0.6041, P = 0.0102). Patients who had a documented partial response were more likely to have an increase in p-Akt T308 with treatment compared with nonresponders (P = 0.0146). CONCLUSION: PIK3CA/PTEN genomic aberrations and high p-Akt levels are associated with rapamycin sensitivity in vitro. Rapamycin-mediated Akt activation is greater in RS cells, with a similar observation in patients with clinical responses on exploratory biomarker analysis; thus feedback loop activation of Akt is not a marker of resistance but rather may function as an indicator of rapamycin activity.