Predicting Nodal Positivity in Women 70 Years of Age and Older with Hormone Receptor-Positive Breast Cancer to Aid Incorporation of a Society of Surgical Oncology Choosing Wisely Guideline into Clinical Practice.

PURPOSE: One of the Society of Surgical Oncology Choosing Wisely guidelines recommends avoiding routine sentinel lymph node (SLN) surgery in clinically node-negative women ≥70 years of age with hormone receptor-positive (HR+) breast cancer. We sought to assess the impact of tumor stage and grade on nodal positivity, and to develop a model to identify patients at low-risk of nodal positivity to aid adoption of the guideline. METHODS: We identified women ≥70 years of age with HR+ cN0 invasive breast cancer in the National Cancer Database (NCDB; 2010-2013) and examined the impact of tumor stage and grade on nodal positivity to identify low-risk combinations. A multivariable logistic regression model was developed to incorporate additional factors. The area under the curve (AUC) and relative risks (RR) were used to assess performance. RESULTS: Among 71,834 cases, the pathologic nodal positivity (pN+) rate was 15.3%. We identified low-risk criteria as grade 1, cT1mi-T1c (≤2.0 cm), or grade 2, cT1mi-T1b (≤1.0 cm), with pN+ rates of 7.8% compared with 22.3% in patients not meeting these criteria (RR 2.86, p < 0.001). On multivariable analysis, factors associated with pN+ status included clinical T stage, grade, and histology (each p < 0.001). The resulting model had AUC 0.70 and identified women with low predicted probability (<10%) of positive nodes, of whom 6.3% were pN+, versus 21.2% in those with predicted probability ≥10% (RR 3.34, p < 0.001). CONCLUSION: The simple clinical rule (grade 1, cT1mi-T1c, or grade 2, cT1mi-T1b), as well as the predictive model, both identify women at low risk of nodal positivity where SLN surgery can be omitted.

Clinical Decision-Making in Patients with Variant of Uncertain Significance in BRCA1 or BRCA2 Genes.

BACKGROUND: How diagnosis with a variant of uncertain significance (VUS) in a BRCA gene impacts clinical decision-making is not well known. METHODS: We queried for all patients attending Mayo Clinic Rochester from 2004 to 2016 who tested positive for BRCA1 or BRCA2 VUS and reviewed patient management choices. Groups were compared by using Wilcoxon rank-sum and Chi-square tests. RESULTS: We identified 97 patients (95 females, 2 males) with BRCA VUS. For patients without cancer history (n = 20), 80% had a mother or sister with breast cancer, and median Tyrer-Cuzick (IBIS) lifetime breast cancer risk score was 27% (range 16-62%). Management included bilateral prophylactic mastectomy (BPM) in 39%, where choice for BPM was significantly associated with IBIS score (median 32 vs. 24%, p = 0.02) and first-degree family history of breast cancer (100 vs. 64%, p = 0.03) but not Gail score or total number of family members with cancer. For patients with breast cancer who had known VUS status prior to surgery (n = 9), the rate of contralateral prophylactic mastectomy (CPM) was 22% compared with 25% without known VUS and 83% with known BRCA pathogenic mutation. In 21 of 97 (22%) patients, the BRCA VUS has been reclassified (95% benign, 5% deleterious). CONCLUSIONS: BRCA VUS carriers with cancer elected surgical choices similar to average-risk breast cancer patients. However, VUS carriers without cancer had high rates of BPM, associated with first-degree family history and IBIS score. Over time, a significant proportion of BRCA VUS were reclassified, illustrating the importance of appropriate counseling regarding VUS.

Is axillary surgery beneficial for patients with adenoid cystic carcinoma of the breast?

BACKGROUND AND OBJECTIVES: Adenoid cystic carcinoma (ACC) is a rare, typically triple-negative, breast cancer reported to have a favorable prognosis and low rate of nodal metastasis. No consensus guidelines exist for axillary staging and treatment. METHODS: We identified all patients with ACC evaluated at our institution from January 1994 to August 2016. Patient, tumor, and treatment variables were abstracted and analyzed. RESULTS: We identified 20 pure ACCs (0.13% of all invasive breast cancers) with size range 0.2-4.8 cm, in 19 women, median age 59 years. Preoperative axillary ultrasound was normal in 10/13 women and suspicious in 3/13 who had a subsequent negative lymph node fine needle aspiration (FNA). Fifteen patients (75%) had sentinel lymph node surgery and were pathologically node-negative, while the remaining five had no axillary surgery. With 3.6 years median follow-up (range 0.2-38.6 years), three patients experienced an in-breast recurrence at 2, 16, and 17 years, respectively, while none recurred in regional nodes. CONCLUSIONS: We observed no cases of nodal metastasis in 20 consecutive cases of ACC of the breast. Preoperative axillary ultrasound with FNA of suspicious nodes accurately predicted pathologic nodal stage. These data suggest axillary surgery might be omitted safely in patients with pure ACC and a clinically negative axilla.

Pharmacological Ascorbate Radiosensitizes Pancreatic Cancer.

The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress-induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer.

Extracellular superoxide dismutase suppresses hypoxia-inducible factor-1α in pancreatic cancer.

Hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcription factor that governs cellular responses to reduced oxygen availability by mediating crucial homeostatic processes and is a major survival determinant for tumor cells growing in a low-oxygen environment. Clinically, HIF-1α seems to be important in pancreatic cancer, as HIF-1α correlates with metastatic status of the tumor. Extracellular superoxide dismutase (EcSOD) inhibits pancreatic cancer cell growth by scavenging nonmitochondrial superoxide. We hypothesized that EcSOD overexpression leads to changes in the O2(-)/H2O2 balance modulating the redox status affecting signal transduction pathways. Both transient and stable overexpression of EcSOD suppressed the hypoxic accumulation of HIF-1α in human pancreatic cancer cells. This suppression of HIF-1α had a strong inverse correlation with levels of EcSOD protein. Coexpression of the hydrogen peroxide-removing protein glutathione peroxidase did not prevent the EcSOD-induced suppression of HIF-1α, suggesting that the degradation of HIF-1α observed with high EcSOD overexpression is possibly due to a low steady-state level of superoxide. Hypoxic induction of vascular endothelial growth factor (VEGF) was also suppressed with increased EcSOD. Intratumoral injections of an adenoviral vector containing the EcSOD gene into preestablished pancreatic tumors suppressed both VEGF levels and tumor growth. These results demonstrate that the transcription factor HIF-1α and its important gene target VEGF can be modulated by the antioxidant enzyme EcSOD.

Manganoporphyrins increase ascorbate-induced cytotoxicity by enhancing H2O2 generation.

Renewed interest in using pharmacological ascorbate (AscH-) to treat cancer has prompted interest in leveraging its cytotoxic mechanism of action. A central feature of AscH- action in cancer cells is its ability to act as an electron donor to O2 for generating H2O2. We hypothesized that catalytic manganoporphyrins (MnP) would increase AscH- oxidation rates, thereby increasing H2O2 fluxes and cytotoxicity. Three different MnPs were tested (MnTBAP, MnT2EPyP, and MnT4MPyP), exhibiting a range of physicochemical and thermodynamic properties. Of the MnPs tested, MnT4MPyP exerted the greatest effect on increasing the rate of AscH- oxidation as determined by the concentration of ascorbate radical [Asc•-] and the rate of oxygen consumption. At concentrations that had minimal effects alone, combining MnPs and AscH- synergized to decrease clonogenic survival in human pancreatic cancer cells. This cytotoxic effect was reversed by catalase, but not superoxide dismutase, consistent with a mechanism mediated by H2O2. MnPs increased steady-state concentrations of Asc•- upon ex vivo addition to whole blood obtained either from mice infused with AscH- or patients treated with pharmacologic AscH-. Finally, tumor growth in vivo was inhibited more effectively by combining MnT4MPyP with AscH-. We concluded that MnPs increase the rate of oxidation of AscH- to leverage H2O2 flux and ascorbate-induced cytotoxicity.

Comparison of response evaluation criteria in solid tumors with volumetric measurements for estimation of tumor burden in pancreatic adenocarcinoma and hepatocellular carcinoma.

BACKGROUND: Response evaluation criteria in solid tumors (RECIST) is the accepted method for determining tumor progression. However, RECIST may not estimate disease burden accurately because the axial plane often does not produce the actual longest diameter. Volumetric measurements may be an alternative to better determine tumor size. Our aim was to compare volumetric measurements with RECIST in pancreatic ductal adenocarcinomas (PDA) and hepatocellular carcinomas (HCC). METHODS: RECIST and volumetric measurements were determined in 9 patients with metastatic PDA and 17 patients with HCC who subsequently underwent liver transplantation. Gross pathologic measurements after hepatectomy also were analyzed for volumes. RESULTS: Three-dimensional diameter in volumetric analysis was 38% and 36% higher than RECIST diameter in PDA and HCC, respectively (P < .01). However, RECIST yielded 78% and 23% larger estimated tumor volumes than volumetric analysis in PDA and HCC, respectively (P < .01). Gross pathologic volume in HCC showed a linear correlation with both volumetric analysis (r = .95; P < .01) and RECIST (r = .96; P < .01) but RECIST significantly overestimated gross pathologic volume by an average of 28% (P < .01) whereas volumetric analysis was similar to gross pathologic volume (P = .56). In categorizing treatment response in PDA, RECIST and volumetric analysis were in moderate agreement (κ = .49). CONCLUSIONS: RECIST significantly may overestimate tumor burden compared with volumetric measurements in both PDA and HCC. Volumetric analysis may be the preferred method to detect tumor progression.