BACKGROUND: The 2015 National Comprehensive Cancer Network guidelines recommend that genetic counseling and germline BRCA mutation testing be offered to women under age 60 with triple‐negative breast cancer (TNBC). As a result of the 2010 American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines for breast cancer, patients with breast cancers that are estrogen receptor (ER) or progesterone receptor (PR) low‐positive (1%‐9% on immunohistochemistry) are no longer strictly considered to have TNBC and may not be referred for genetic counseling. However, the incidence of BRCA mutation in patients with hormone receptor (HR) low‐positive breast cancers remains unknown, and current ASCO/CAP guidelines may result in undertesting for BRCA mutations.METHODS: A prospectively maintained research database of breast cancer patients evaluated at The University of Texas MD Anderson Cancer Center between 2004 and 2014 was reviewed; 314 patients were identified with HER2/neu–negative breast cancers expressing ER and PR <10% with known BRCA mutation status.RESULTS: Three hundred fourteen patients had breast cancers expressing ER and PR <10%; 238 (75.8%) had HR‐negative cancers (<1% ER and PR), and 76 (24.2%) had HR–low‐positive cancers (1%‐9% ER and/or PR). Among patients with HR‐negative tumors, 86 of 238 (36.1%) had a BRCA1/2 mutation, whereas in the HR–low‐positive group, 30 of 76 (39.5%) had a BRCA1/2 mutation. In multivariate analysis, HR status (<1% vs 1%‐9%) was not significantly associated with BRCA1/2 mutations.CONCLUSIONS: The incidence of BRCA1/2 mutations is similar in patients with HR–low‐positive breast cancer and patients with HR‐negative breast cancer. Genetic counseling and BRCA testing should be offered to patients under age 60 who have HR–low‐positive breast cancers. Cancer 2015;121:3435–43. © 2015 American Cancer Society.

N-Myc downstream regulated gene 1 (NDRG1) suppresses metastasis in many human malignancies, including breast cancer, yet has been associated with worse survival in patients with inflammatory breast cancer. The role of NDRG1 in the pathobiology of aggressive breast cancers remains elusive. To study the role of NDRG1 in tumor growth and brain metastasis in vivo, we transplanted cells into cleared mammary fat pads or injected them in tail veins of SCID/Beige mice (n = 7-10 per group). NDRG1 protein expression in patient breast tumors (n = 216) was assessed by immunohistochemical staining. Kaplan-Meier method with 2-sided log-rank test was used to analyze the associations between NDRG1 and time-to-event outcomes. A multivariable Cox regression model was used to determine independent prognostic factors. All statistical tests were 2-sided. We generated new sublines that exhibited a distinct propensity to metastasize to the brain. NDRG1-high–expressing cells produced more prevalent brain metastases (100% vs 44.4% for NDRG1-low sublines, P = .01, Fisher’s exact test), greater tumor burden, and reduced survival in mice. In aggressive breast cancer cell lines, silencing NDRG1 led to reduced migration, invasion, and tumor-initiating cell subpopulations. In xenograft models, depleting NDRG1 inhibited primary tumor growth and brain metastasis. In patient breast tumors, NDRG1 was associated with aggressiveness: NDRG1-high expression was also associated with shorter overall survival (hazard ratio [HR] = 2.27, 95% confidence interval [95% CI] = 1.20 to 4.29, P = .009) and breast cancer–specific survival (HR = 2.19, 95% CI = 1.07 to 4.48, P = .03). Multivariable analysis showed NDRG1 to be an independent predictor of overall survival (HR = 2.17, 95% CI = 1.10 to 4.30, P = .03) and breast cancer–specific survival rates (HR = 2.27, 95% CI = 1.05 to 4.92, P = .04). We demonstrated that NDRG1 drives tumor progression and brain metastasis in aggressive breast cancers and that NDRG1-high expression correlates with worse clinical outcomes, suggesting that NDRG1 may serve as a therapeutic target and prognostic biomarker in aggressive breast cancers.

Background: Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of 5′-AMP-activated protein kinase (AMPK) suggesting combination therapy may enhance antitumor activity of sapanisertib. We report preliminary safety, tolerability, and efficacy from the dose-escalation study of sapanisertib in combination with metformin in patients with advanced solid tumors. Methods: Patients with advanced metastatic solid tumors resistant or refractory to standard treatment, with and without mTOR/AKT/PI3K pathway alterations, received sapanisertib 3 or 4 mg daily together with metformin once to three times daily (500–1,500 mg). All patients underwent 14-day titration period for metformin in cycle 1. Tumor measurements were performed following cycle 2 and subsequently every 8 weeks. Results: A total of 30 patients were enrolled across four cohorts (3 mg/500 mg; 3 mg/1,000 mg, 4 mg/1,000 mg; 4 mg/1,500 mg). 19 were female (63%), median age was 57 (range: 30–77), all were Eastern Cooperative Oncology Group performance status 1. Tumor types included sarcoma (6), breast (4), ovarian (4), head and neck (3), colorectal (2), lung (2), renal cell (2), endometrial (2), gastroesophageal junction (1), prostate (1), stomach (1), urachus (1), and cervical cancer (1). Median number of prior lines of therapy was 4. Most common genomic alterations included PIK3CA (27%), PTEN (17%), AKT1/2 (10%), mTOR (10%). Of 30 patients evaluable for response, 4 patients achieved partial response (PR); 15 patients achieved stable disease (SD) as best response. Disease control rate (PR+SD) was 63%. Of the responders in PR, 3 of 4 patients had documented PTEN mutations (3/5 patients enrolled with PTEN mutations had PR); 2 of 4 of patients in PR had comutations (patient with leiomyosarcoma had both PTEN and TSC; patient with breast cancer had both PTEN and STK11); 1 of 4 patients in PR had AKT and mTOR mutation; tumor types included leiomyosarcoma (n = 2), breast (n = 1), and endometrial cancer (n = 1). Most common treatment-emergent adverse events included nausea, anorexia, diarrhea, and rash. Grade (G) 3–5 treatment-related adverse events included hyperglycemia (4/30; 13%), fatigue (2/30; 7%), hypertriglyceridemia (1/30; 3%), rash (2/20; 7%), diarrhea (2/30; 7%), creatinine increase (1/30; 3%), acidosis (1/30; 3%). No dose-limiting toxicities (DLT) were reported in the 3 mg/500 mg cohort. One of 6 patient had DLT in the 3 mg/1,000 mg cohort (G3 diarrhea) and 2 of 11 patients had DLTs in the 4 mg/1,500 mg cohort (G3 fatigue, G3 rash). 4 mg/1,000 mg was defined as the MTD. Conclusions: The safety profile of mTORC1/2 inhibitor sapanisertib in combination with metformin was generally tolerable, with antitumor activity observed in patients with advanced malignancies harboring PTEN mutations and AKT/mTOR pathway alterations. Significance: Sapanisertib (CB-228/TAK-228) is a potent, selective ATP-competitive, next-generation dual inhibitor of mTORC1/2. Metformin is thought to inhibit the mTOR pathway through upstream activation of AMPK suggesting combination therapy may enhance antitumor activity of sapanisertib. This dose-escalation study of sapanisertib and metformin in advanced solid tumors and mTOR/AKT/PI3K pathway alterations, demonstrates safety, tolerability, and early clinical activity in advanced malignancies harboring PTEN mutations and AKT/mTOR pathway alterations. Clinical trial information: NCT03017833

Background : Ten to fourteen percent of Ewing sarcoma (ES) study participants treated nationwide with IGF-1 receptor (IGF-1R)-targeted antibodies achieved tumor regression. Despite this success, low response rates and short response durations (approximately 7-weeks) have slowed the development of this therapy. Methods: We performed a meta-analysis of five phase-1b/2 ES-oriented trials that evaluated the anticancer activity of IGF-1R antibodies +/− mTOR inhibitors (mTORi). Our meta-analysis provided a head-to-head comparison of the clinical benefits of IGF-1R antibodies vs. the IGF-1R/mTOR-targeted combination. Available pretreatment clinical samples were semi-quantitatively scored using immunohistochemistry to detect proteins in the IGF-1R/PI3K/AKT/mTOR pathway linked to clinical response. Early PET/CT imaging, obtained within the first 2 weeks (median 10 days), were examined to determine if reduced FDG avidity was predictive of progression-free survival (PFS). Results: Among 56 ES patients treated at MD Anderson Cancer Center (MDACC) with IGF-1R antibodies, our analysis revealed a significant ~two-fold improvement in PFS that favored a combination of IGF-1R/mTORi therapy (1.6 vs. 3.3-months, p = 0.042). Low pIGF-1R in the pretreatment specimens was associated with treatment response. Reduced total-lesion glycolysis more accurately predicted the IGF-1R response than other previously reported radiological biomarkers. Conclusion: Synergistic drug combinations, and newly identified proteomic or radiological biomarkers of IGF-1R response, may be incorporated into future IGF-1R-related trials to improve the response rate in ES patients.

Background: Computed tomography to body divergence (CTBD) is one of the main barriers to bronchoscopic techniques for the diagnosis of peripherally located lung nodules. Cone-beam CT (CBCT) guidance is being rapidly adopted to correct for this phenomenon and to potentially increase diagnostic outcomes. In this trial, we hypothesized that the addition of mobile CBCT (m-CBCT) could improve the rate of tool in lesion (TIL) and the diagnostic yield of shape-sensing robotic-assisted bronchoscopy (SS-RAB). Methods: This was a prospective, single-arm study, which enrolled patients with peripheral lung nodules of 1–3 cm and compared the rate of TIL and the diagnostic yield of SS-RAB alone and combined with mCBCT. Results: A total of 67 subjects were enrolled, the median nodule size was 1.7 cm (range, 0.9–3 cm). TIL was achieved in 23 patients (34.3%) with SS-RAB alone, and 66 patients (98.6%) with the addition of mCBCT (p < 0.0001). The diagnostic yield of SS-RAB alone was 29.9% (95% CI, 29.3–42.3%) and it was 86.6% (95% CI, 76–93.7%) with the addition of mCBCT (p < 0.0001). There were no pneumothoraxes or any bronchoscopy-related complications, and the median total dose–area product (DAP) was 50.5 Gy-cm². Conclusions: The addition of mCBCT guidance to SS-RAB allows bronchoscopists to compensate for CTBD, leading to an increase in TIL and diagnostic yield, with acceptable radiation exposure.

NDRG1 is widely described as a metastasis suppressor in breast cancer. However, we found that NDRG1 is critical in promoting tumorigenesis and brain metastasis in mouse models of inflammatory breast cancer (IBC), a rare but highly aggressive form of breast cancer. We hypothesized that NDRG1 is a prognostic marker associated with poor outcome in patients with IBC. NDRG1 levels in tissue microarrays from 64 IBC patients were evaluated by immunohistochemical staining with NDRG1 (32 NDRG1-low (≤median), 32 NDRG1-high (>median)). Overall and disease-free survival (OS and DSS) were analyzed with Kaplan–Meier curves and log-rank test. Univariate analysis showed NDRG1 expression, tumor grade, disease stage, estrogen receptor (ER) status, and receipt of adjuvant radiation to be associated with OS and DSS. NDRG1-high patients had poorer 10-year OS and DSS than NDRG1-low patients (OS, 19% vs. 45%, p = 0.0278; DSS, 22% vs. 52%, p = 0.0139). On multivariable analysis, NDRG1 independently predicted OS (hazard ratio (HR) = 2.034, p = 0.0274) and DSS (HR = 2.287, p = 0.0174). NDRG1-high ER-negative tumors had worse outcomes OS, p = 0.0003; DSS, p = 0.0003; and NDRG1-high tumors that received adjuvant radiation treatment had poor outcomes (OS, p = 0.0088; DSS, p = 0.0093). NDRG1 was a significant independent prognostic factor for OS and DSS in IBC patients. Targeting NDRG1 may represent a novel strategy for improving clinical outcomes for patients with IBC.