SuEllen J. Pommier

Incidence and outcomes of contralateral breast cancers

BACKGROUND The significance of a contralateral breast cancer is largely unknown, making prophylactic mastectomy controversial. METHODS Differences between stages of initial and contralateral cancers were determined by t test. Survival distributions were compared by log-rank analyses and compared with Surveillance Epidemiology and End Results data for unilateral cancers. RESULTS Metachronous contralateral cancers occurred at a rate of .13% per year and were of significantly lower stage. Metachronous cancers adversely impacted survival for patients with low-stage initial cancers, but the interval between cancers was less than 36 months. Synchronous tumors occurred in 2.3% of patients; survival was worse than for patients with metachronous cancers. CONCLUSIONS Prophylactic mastectomy is unlikely to be beneficial because of the lower stages and low incidence of second cancers, even for patients with initial low-stage cancers.

Hepatic artery chemoinfusion with chemoembolization for neuroendocrine cancer with progressive hepatic metastases despite octreotide therapy.

BACKGROUND Hepatic metastases from neuroendocrine cancer dramatically reduce survival, introducing an important opportunity for intervention. Several treatment modalities have been examined, but an optimal treatment approach has been difficult to define. We evaluated a regimen combining hepatic artery chemoinfusion with chemoembolization. METHODS Patients with neuroendocrine cancer and diffuse hepatic metastases were treated with hepatic artery chemoinfusion and chemoembolization when they demonstrated disease progression despite octreotide therapy. Four monthly cycles of 5-fluorouracil were administered via hepatic artery infusion with chemoembolization after the final 2 cycles. Response was defined by radiologic response or symptomatic improvement. RESULTS Seventy-seven patients were treated; 18 received chemoinfusion only. The treatment-related mortality rate was 7%. The overall response rate was 80% for patients with carcinoid or islet cell neoplasms. Median progression-free survival was 19 months. Median disease-specific survival was 39 months from the first treatment; 1- and 5-year survival rates were 78% and 27%, respectively. CONCLUSION Survival after initiating this regimen was over 3 years for the majority of patients exhibiting progression of extensive, unresectable hepatic disease despite octreotide therapy. The addition of hepatic artery chemoinfusion to chemoembolization offers a high probability of clinical benefit to patients who, otherwise, have severely limited therapeutic options and a dismal survival.

Octreotide LAR and bolus octreotide are insufficient for preventing intraoperative complications in carcinoid patients

Surgery in carcinoid patients can provoke a carcinoid crisis, which can have serious sequelae, including death. Octreotide prophylaxis is recommended to prevent carcinoid crisis, however there are few reports of outcomes and no large series examining its efficacy. We hypothesized that a 500 µg prophylactic octreotide dose is sufficient to prevent carcinoid crisis.

A new hormonal therapy for estrogen receptor-negative breast cancer.

BackgroundWe postulate that the androgen dehydroepiandrosterone sulfate (DHEAS) may represent an innovative hormonal treatment for estrogen (ER), progesterone (PR) receptor–negative, but androgen receptor (AR)–positive breast cancers by inhibiting breast cancer cell growth through AR stimulation.MethodsThree ER,PR–negative breast cancer cell lines (HCC 1137, 1954, and 38), were treated with DHEAS. DHEAS-induced growth was measured by a methylthiotetrazole (MTT) proliferation assay and apoptosis by TUNEL fluorescence. Androgen receptor gene expression levels were determined using quantitative real-time polymerase chain reaction (q-RT-PCR).ResultsHCC cell lines 1954 and 1937 were positive for AR expression; HCC 38 was weakly positive. MTT analysis showed DHEAS-induced decreases in cell proliferation of 47% in HCC 1937, 27% in HCC 1954, and 0.4% in HCC 38. Ten days of culturing HCC 1954 cells after the removal of DHEAS resulted in a 3.5-fold increase in growth. Continuous treatment for the same duration induced a 2.8-fold decrease in growth. Parallel experiments showed no significant changes in HCC 38 cultures. TUNEL assays showed DHEAS-induced apoptosis fold increases of 2.8 in HCC 1937, 1.9 in HCC 1954, and no significant difference in HCC 38 cultures. Q-RT-PCR of HCC 1954 cells showed a 6-fold DHEAS-induced decrease in AR gene expression at 4 h. Co-treatment with Casodex nullified this effect.ConclusionsDHEAS inhibited growth of ER,PR–negative, AR–positive breast cancer cells. DHEAS was cytotoxic to these breast cancer cells via the apoptosis pathway. DHEAS may be an effective treatment for a population previously excluded from hormone therapy.

Expanded criteria for carcinoid liver debulking: Maintaining survival and increasing the number of eligible patients

BACKGROUND Cytoreduction of carcinoid liver metastases typically aims for ≥ 90% debulking in patients without extrahepatic disease. Data on the impact of less-restrictive resection criteria and other clinical and tumor-specific factors on outcomes are limited. METHODS Records of carcinoid patients undergoing liver debulking from 2007 to 2011 were reviewed. Debulking threshold was 70%, extrahepatic disease did not preclude cytoreduction, and positive margins were allowed. Kaplan-Meier liver progression-free (PFS) and disease-specific (DSS) survival were calculated and compared by log-rank analysis and statistical significance of differences in distributions of factors between patient groups was determined by chi-squared analysis. RESULTS Fifty-two patients were identified. Complete resection of intrahepatic and extrahepatic gross disease was achieved in 12 patients. All primaries reviewed were low grade, but one third of patients had at least one intermediate-grade metastasis. Fifteen patients (29%) had liver progression; median PFS was 72 months. Five-year DSS was 90%, with all deaths from liver failure. Only age was an important prognostic factor for PFS and DSS. Five-year DSS for patients <50 years was 73% and was 97% for patients 50 or older (P = .03). CONCLUSION The use of expanded criteria for debulking resulted in 90% 5-year DSS. Although younger age portends a poorer prognosis, the favorable PFS and DSS justify also using expanded criteria in this subgroup.

Improved breast cancer survival among hormone replacement therapy users is durable after 5 years of additional follow-up

BACKGROUND We previously reported that breast cancer patients who used hormone replacement therapy (HRT) had significantly lower stage tumors and higher survival than never-users. We present an update with longer follow-up, HRT use data, and in vitro research. METHODS Our database of 292 postmenopausal breast cancer patients was updated to include HRT type, duration, and disease status. In vitro effects of estrogen (E) and/or medroxyprogesterone (MPA) on breast cancer cell growth were measured. RESULTS Tumor prognostic factors were better and survival rates higher for both E and combination HRT users of any duration. Use greater than 10 years correlated with node-negative disease, mammographically detected tumors, and 100% survival. E supported minimal proliferation; MPA induced cell death; E+MPA results were similar to E alone. CONCLUSIONS HRT users, regardless of type or duration of HRT use, continued to have higher survival rates. In vitro results supported the clinical finding that outcomes for users of E and E+MPA were similar.

Continuous infusion of octreotide combined with perioperative octreotide bolus does not prevent intraoperative carcinoid crisis.

BACKGROUND Operations and anesthesia in carcinoid patients can provoke carcinoid crises, which can have serious sequelae, including death. Prophylactic octreotide is recommended to prevent crises. Recommended prophylaxis regimens vary from octreotide long-acting repeatable to preoperative bolus to continuous octreotide infusion; however, efficacy data are lacking. We have shown previously that crises correlated with major complications and that octreotide long-acting repeatable and preoperative bolus failed to prevent crises. This study examines the impact of continuous octreotide infusion. METHODS A total of 127 patients (71% with liver metastases, 74% with carcinoid syndrome) who underwent 150 operations with continuous octreotide infusions were enrolled in this prospective case series. Our main outcome measures were the occurrence of intraoperative carcinoid crises and post-operative complications. RESULTS Crises occurred at a rate of 30% as compared with 24% in our previous series, which examined the impact of preoperative octreotide bolus. Crises were significantly associated with the presence of hepatic metastases (P = .02) or history of carcinoid syndrome (P = .006), although neither was required for crises. Prompt vasopressor treatment shortened the mean duration of hypotension to 8.7 minutes, compared with 19 minutes in our prior series. Crises no longer correlated with major complications (P = .481) unless instability persisted for greater than 10 minutes (P = .011). CONCLUSION Octreotide infusions do not prevent intraoperative crises. Patients without liver metastases or carcinoid syndrome can have intraoperative crises. Postoperative complications can be decreased by reducing the duration of crises. Further study is needed to determine how best to shorten hemodynamic instability during crises.

Laparoscopic surgical exploration is an effective strategy for locating occult primary neuroendocrine tumors

BACKGROUND Many patients with neuroendocrine tumors (NETs) have metastases at diagnosis. Despite extensive metastases the primary tumors remain small and difficult to locate. METHODS Records of patients diagnosed with metastatic abdominal NETs from 2006 to 2010 were reviewed retrospectively. Results of preoperative imaging, procedures, and surgical explorations were compared for their efficacy at finding primary tumors. RESULTS Sixty-three patients were identified. Seventeen percent (11 of 63) of tumors were located by preoperative testing. The sensitivities of preoperative colonoscopy (23% [n = 26]), computed tomography scan (6.7% [n = 60]), and somatostatin receptor scintigraphy (2.0% [n = 52]) were low. No tumors were found by magnetic resonance imaging (n = 9), upper endoscopy (n = 24), capsule endoscopy (n = 2), or bronchoscopy (n = 4). Surgical exploration was the most sensitive (79% [n = 63]) method of tumor detection. Seventy-two percent of surgical localizations were laparoscopic. CONCLUSIONS Surgical exploration was superior to all other modalities for locating primary NETs. Laparoscopy had a high probability of finding occult primary neuroendocrine tumors.

Correlation of Breast Cancer Axillary Lymph Node Metastases With Stem Cell Mutations

IMPORTANCE Mutations in oncogenes AKT1, HRAS, and PIK3CA in breast cancers result in abnormal PI3K/Akt signaling and tumor proliferation. They occur in ductal carcinoma in situ, in breast cancers, and in breast cancer stem and progenitor cells (BCSCs). OBJECTIVES To determine if variability in clinical presentation at diagnosis correlates with PI3K/Akt mutations in BCSCs and provides an early prognostic indicator of increased progression and metastatic potential. DESIGN, SETTING, AND PARTICIPANTS Malignant (BCSCs) and benign stem cells were collected from fresh surgical specimens via cell sorting and tested for oncogene mutations in a university hospital surgical oncology research laboratory from 30 invasive ductal breast cancers (stages IA through IIIB). MAIN OUTCOMES AND MEASURES Presence of AKT1, HRAS, and PIK3CA mutations in BCSCs and their correlation with tumor mutations, pathologic tumor stage, tumor histologic grade, tumor hormone receptor status, lymph node metastases, and patient age and condition at the last follow-up contact. RESULTS Ten tumors had mutations in their BCSCs. In total, 9 tumors with BCSC mutations and 4 tumors with BCSCs without mutations had associated tumor present in the lymph nodes (P = .001). CONCLUSIONS AND RELEVANCE Tumors in which BCSCs have defects in PI3K/Akt signaling are significantly more likely to manifest nodal metastases. These oncogenic defects may be missed by gross molecular testing of the tumor and are markers of more aggressive breast cancer. Molecular profiling of BCSCs may identify patients who would likely benefit from PI3K/Akt inhibitors, which are being tested in clinical trials.

Fresh Surgical Specimens Yield Breast Stem/Progenitor Cells and Reveal Their Oncogenic Abnormalities

BackgroundThe process by which breast cancer stem cells arise is unknown. It may be that the benign stem cells in breast tissue are transformed into malignant stem cells through the acquisition of genetic abnormalities. In this study, we collected and compared benign and malignant breast stem/progenitor cells to determine whether specific genetic abnormalities occur in breast cancer stem/progenitor cells within the human body.MethodsFresh surgical specimens from benign and malignant breast tissues were obtained directly from the operating room and examined. Cells variably expressing stem cell-associated surface markers CD49f and CD24 were collected by fluorescence-activated cell sorting. The frequencies of these cells in benign and malignant breast tissues were ascertained. Oncogenetic mutation analyses were performed and expression of stem cell-associated genes was measured.ResultsThe frequencies of stem/progenitor cells were similar between benign and malignant tissues. Stem cell-associated gene expression also was similar between benign and malignant stem cells. Genetic mutations in the PIK/AKT pathway were found in 73% of the tumors’ stem cells, specifically within two subpopulations. No mutations were found in stem/progenitor cell subpopulations from benign breast tissue.ConclusionsThe results of this study suggest that, following malignant transformation, breast cancer stem/progenitor cells retain their stem cell functions and relative frequencies. In addition, they develop malignant capabilities by acquiring mutations in genes critical for maintaining normal cellular metabolism and proliferation.