Nathaniel Bouganim

Granulocyte-Macrophage Colony-Stimulating Factor and Interleukin-2 Fusion cDNA for Cancer Gene Immunotherapy

Genetic engineering of tumor cells to express both granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-2 can induce synergistic immune antitumor effects. Paradoxically, the combination has also been reported to down-regulate certain immune functions, highlighting the unpredictability of dual cytokine use. We hypothesized that a GM-CSF and IL-2 fusion transgene (GIFT) could circumvent such limitations yet preserve synergistic features. We designed a fusion cDNA of murine GM-CSF and IL-2. Protein structure computer modeling of GIFT protein predicted for intact ligand binding domains for both cytokines. B16 mouse melanoma cells were gene modified to express GIFT (B16GIFT), and these cells were unable to form tumors in C57bl/6 mice. Irradiated B16GIFT whole-cell tumor vaccine could also induce absolute protective immunity against challenge by live B16 cells. In mice with established melanoma, B16GIFT therapeutic cellular vaccine significantly improved tumor-free survival when compared with B16 expressing both IL-2 and GM-CSF. We show that GIFT induced a significantly greater tumor site recruitment of macrophages than combined GM-CSF and IL-2 and that macrophage recruitment arises from novel chemotactic feature of GIFT. In contrast to suppression by GM-CSF of natural killer (NK) cell recruitment despite coexpression of IL-2, GIFT leads to significant functional NK cell infiltration as confirmed in NK-defective beige mice. In conclusion, we demonstrated that a fusion between GM-CSF and IL-2 can invoke greater antitumor effect than both cytokines in combination, and novel immunobiological properties can arise from such chimeric constructs.

Use of Conjoint Analysis to Assess Breast Cancer Patient Preferences for Chemotherapy Side Effects

OBJECTIVE Our objective was to evaluate preferences associated with grade I/II and grade III/IV chemotherapy side effects among breast cancer patients receiving chemotherapy. We also assessed trade-offs that patients are willing to make between treatment side effects and the route and schedule of treatment administration. METHODS In this cross-sectional study, patients receiving chemotherapy for breast cancer completed a one-time Web survey. Conjoint analysis was used to elicit preferences for 17 grade I/II and III/IV side effects associated with available chemotherapies and regimens. In the analysis, the risk of each side effect was increased by 5%, holding all others constant, and the respective impact on patient preferences was identified. RESULTS A total of 102 women participated (mean age 54 ± 11). Among the grade I/II side effects, a 5% reduction in the risk of sensory neuropathy, nausea, and motor neuropathy had the highest impact on preferences. Among grade III/IV side effects, motor neuropathy, nausea/vomiting, and myalgia made the most difference. An oral twice-daily regimen was most preferred; however, patients were willing to receive an intravenous regimen relative to oral to avoid an increased risk of 5% in the majority of side effects. Avoiding an increased chance of grade III/IV motor neuropathy was associated with willingness to tolerate one of the least preferred administration schedules. CONCLUSION This study identified relative preferences among both mild/moderate to severe side effects from the patient perspective. Patients appear to be willing to make trade-offs between side effects and different regimens. These findings may help to inform medical decision-making processes.

Bone-targeted agents in the treatment of bone metastases: RANK outsider or new kid on the block?

Stopeck AT, Lipton A, Body JJ et al.: Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. Clin. Oncol. 28(35), 5132-5139 (2010). Bone is the most common site of recurrence in patients with advanced breast cancer. Bisphosphonates have revolutionized the care for patients with bone metastases by delaying and reducing skeletal complications. The RANK ligand inhibitor denosumab has been developed as a result of our enhanced understanding of bone physiology. In a recent randomized, double-blind trial, denosumab has been shown to be superior to zoledronic acid in delaying the onset of skeletal complications in advanced breast cancer patients. While these results are exciting, the absence of any survival benefit and the considerable cost of this agent mean that further quality-of-life data are needed before it becomes widely used as a new standard of care.

Use of Calcium Channel Blockers and Risk of Breast Cancer: A Population-based Cohort Study.

Background: Several observational studies have associated use of calcium channel blockers with an increased risk of breast cancer, but this association remains controversial. The objective of this study was to determine whether these drugs are associated with an increased risk of breast cancer overall, and to assess whether this risk varies with cumulative duration of use. Methods: We identified a cohort of 273,152 women newly treated with antihypertensive drugs between 1 January 1995 and 31 December 2009, followed until 31 December 2010, using the UK Clinical Practice Research Datalink. We treated calcium channel blocker use as a time-varying variable, and lagged exposure by 1 year for latency considerations and to minimize reverse causality. We used time-dependent Cox proportional hazards models to estimate adjusted hazard ratios with 95% confidence intervals of incident breast cancer associated with use of calcium channel blockers overall and by cumulative duration of use (<5, 5–10, and ≥10 years). Results: During 1,567,104 person-years of follow-up, 4,520 women were newly diagnosed with breast cancer (incidence rate: 2.9 per 1,000 per year). Compared with use of other antihypertensive drugs, use of calcium channel blockers was not associated with increased risk of breast cancer overall (hazard ratio: 0.97, 95% confidence interval: 0.91, 1.03). Similarly, there was no evidence of a duration–response relationship in terms of cumulative duration of use (P trend = 0.26). Conclusions: The results of this large population-based study indicate that long-term use of calcium channel blockers is not associated with an increased risk of breast cancer.

Investigating the discernible and distinct effects of platinum‑based chemotherapy regimens for metastatic triple‑negative breast cancer on time to progression

Platinum-based chemotherapy regimens are frequently used in patients with triple-negative breast cancer (TNBC). The aim of the current study was to assess whether or not platinum-based chemotherapy is associated with an increased time to progression when compared with non-platinum-based regimens in TNBC and non-TNBC. A retrospective analysis was conducted within a cohort of patients with metastatic breast cancer who received platinum-based chemotherapy at a single institution. Data were collected for up to three lines of treatment for metastatic disease. Time to progression was determined for platinum-based chemotherapy and non-platinum-based regimens for each line of treatment. Adjusted hazard ratios (HRs), together with 95% confidence intervals (CIs) were estimated comparing the time to progression associated with the use of platinum-based chemotherapy versus non-platinum-based regimens. A total of 159 patients were included in the analysis, with 58 diagnosed with TNBC. Among the patients with TNBC, compared with non-platinum-based chemotherapy, no correlation was identified between platinum-based chemotherapy and an improved time to progression [first line: HR, 0.97 (95% CI, 0.40–2.35); second line: HR, 0.91 (95% CI, 0.42–2.01); and third line: HR, 2.83 (95% CI, 0.73–11.03)]. By contrast, patients with non-TNBC appeared to improve with non-platinum-based chemotherapy [first line: HR, 2.57 (95% CI, 1.11–5.99); second line: HR, 1.91 (95% CI, 1.00–3.63); and third line: HR, 1.08 (95% CI, 0.53–2.18)]. Although the present study was limited by the sample size and its observational nature, the results indicated that platinum-based chemotherapy does not offer a discernible or distinct advantage compared with standard regimens in patients with TNBC, and is perhaps less efficacious in patients with non-TNBC.

A Case of Recurrent Anaplastic Meningioma of the Skull Base with Radiologic Response to Hydroxyurea

Anaplastic meningiomas are rare and aggressive tumors with a high propensity for local recurrence. Surgical resection and postoperative radiotherapy are the standard of care for primary disease and local recurrences. Refractory disease is managed with chemotherapy with limited success. A highly efficacious, well-tolerated chemotherapeutic agent has yet to be found for this disease entity. Hydroxyurea is currently receiving renewed attention because of its efficacy in inducing apoptosis of meningioma cells in vitro and its favorable side-effect profile. Thus far, in humans, this agent has only induced stable disease. We describe the first patient showing a near complete/partial clinical and radiological regression after 5 months of 25 mg/kg of hydroxyurea once daily, given within 1 month after stereotactic fractionated reirradiation of a previously irradiated and operated anaplastic meningioma of the skull base. Magnetic resonance imaging showed a significant and sustained response with tumor shrinkage and cavitation.

The use of drugs acting on the renin–angiotensin system and the incidence of pancreatic cancer

Background:Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are commonly used antihypertensives. Recently, these drugs have been associated with a protective effect against pancreatic cancer, but data on this putative association remain limited. Thus, the objective of this study was to determine whether the use of ACEIs and/or ARBs is associated with a decreased risk of pancreatic cancer.Methods:We conducted a population-based cohort study, using a nested case–control analysis within the UK Clinical Practice Research Datalink population. The cohort consisted of all patients newly treated with antihypertensive drugs between 1 January 1995 and 31 December 2009, with follow-up until 31 December 2010. Cases were patients with newly diagnosed pancreatic cancer, which were matched with up to 10 controls on age, sex, calendar year of cohort entry, and duration of follow-up. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of pancreatic cancer incidence associated with ever use of ACEIs and ARBs. A secondary analysis was conducted to assess whether the incidence of pancreatic cancer varied with cumulative duration of use of these drugs.Results:A cohort of 547 566 was assembled. During 3 040 332 person-years of follow-up, a total of 866 patients were newly diagnosed with pancreatic cancer (rate: 3/10 000 per year) and matched to 8636 controls. Overall, when compared with other antihypertensive drugs, the use of ACEIs was not associated with a decreased risk of pancreatic cancer overall (OR: 1.01, 95% CI: 0.86–1.17) or according to cumulative duration of use. The use of ARBs was not associated with a decreased risk of pancreatic cancer overall (OR: 0.93, 95% CI: 0.75–1.15), whereas a cumulative duration of use of 1–3 years was associated with a 38% decrease (OR: 0.62, 95% CI: 0.41–0.94), which returned to the null after >3 years of use (OR: 1.04, 95% CI: 0.74–1.46).Conclusions:The use of ARBs and ACEIs was not associated with an overall decreased risk of pancreatic cancer when compared with patients using other antihypertensive drugs. Additional research is needed to determine whether ARBs may confer a short-term protective effect.

Reflex Testing for Germline BRCA1, BRCA2, PALB2, and ATM Mutations in Pancreatic Cancer: Mutation Prevalence and Clinical Outcomes From Two Canadian Research Registries

PurposeWe investigated the translational value of reflex testing for germline mutations in four homology-directed DNA repair predisposition genes (BRCA1, BRCA2, PALB2, and ATM) in consecutive patients with pancreatic adenocarcinoma.MethodsOne hundred fifty patients with French-Canadian (FC) ancestry were evaluated for founder mutations, and 114 patients were subsequently assessed by full gene sequencing and multiplex ligation-dependent probe amplification for nonfounder mutations. Two hundred thirty-six patients unselected for ancestry were also assessed for mutations by full gene sequencing.ResultsThe FC founder mutation prevalence among the 150 patients was 5.3% (95% CI, 2.6% to 10.3%), and the nonfounder mutation prevalence across the four genes among the 114 patients tested was 2.6% (95% CI, 0.6% to 7.8%). In the case series unselected for ancestry, 10.0% (95% CI, 2.7% to 26.4%) of patients reporting Ashkenazi Jewish (AJ) ancestry carried an AJ founder mutation, with no nonfounder mutations identified...

Aromatase inhibitors and the risk of colorectal cancer in postmenopausal women with breast cancer

Background A large trial of postmenopausal women with breast cancer reported an imbalance in colorectal cancer events with aromatase inhibitors (AIs), compared with tamoxifen in the adjuvant setting. This unexpected signal was observed within 3 years of randomization. To date, no observational studies have examined this important safety question in the natural setting of clinical practice. Thus, the objective of this study was to determine whether AIs, when compared with tamoxifen, are associated with increased risk of colorectal cancer in postmenopausal women with breast cancer. Patients and methods Using the UK Clinical Practice Research Datalink, we identified women, at least 55 years of age, with breast cancer newly treated with either AIs or tamoxifen between 1 January 1996 and 30 September 2015, with follow-up until 30 September 2016. High-dimensional propensity score-adjusted Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of incident colorectal cancer associated with AIs when compared with tamoxifen overall, by cumulative duration of use, and time since initiation. All exposures were lagged by 1 year for latency considerations. Results A total of 9701 and 8893 patients initiated AIs and tamoxifen as first-line hormonal therapy (median follow-up of 2.4 and 2.9 years, respectively). Compared with tamoxifen, AIs were not associated with an increased risk of colorectal cancer (incidence rates of 150 per 100 000 person-years in both groups; adjusted HR: 0.90, 95% CI: 0.53-1.52). Similarly, there was no evidence of an association with cumulative duration of use (P-heterogeneity = 0.54), and time since initiation (P-heterogeneity = 0.66). Conclusions In this first population-based study, the use of AIs was not associated with an increased risk of colorectal cancer. These findings should provide reassurance to the concerned stakeholders.

Abstract P3-13-05: Evaluating efficacy of de-escalated bisphosphonate therapy in metastatic breast cancer patients at low-risk of skeletal related events. TRIUMPH: A pragmatic multicentre trial.

Background: Optimal bisphosphonate (BP) dosing intervals for breast cancer patients (pts) with bone metastases (BM) remain unknown. BP are usually prescribed q3-4 wk regardless of individual pt risk for skeletal related events (SREs). Recent evidence (Amadori J Clin Oncol, 2012 suppl; abstr 9005) shows that q12 wk BP is as effective as q4 wk in pts previously treated with >9 cycles of q4 wk therapy. Hence, further evaluation of modified BP dosing strategies is warranted. The objective of the current study was to show in women with biochemically defined low-risk bone disease that IV BP use every q12 wk for 1 year is sufficient to maintain stability of the bone turnover [measured by serum c-telopeptide (CTx) or bone specific alkaline phosphatase (BSAP)]. Methods: Eligible pts with BM, who had received >3 months of q3-4 wk IV BP and no systemic treatment change within 4 wks of study entry were enrolled. Low risk was defined as serum CTx 600 ng/L at baseline, weeks 6, 12, 24, 36 or 48. Evaluation of palliative benefit of 12-wk IV BP therapy was measured by SREs, analgesic use, and self-reported pain (BPI and FACT-BP). Results: Between Oct. 2010-Sept. 2011, 85 pts consented to screening, with 13 found ineligible. In the 71 accrued pts baseline characteristics were: mean age 60 (SD 13), median time from breast cancer diagnosis to development of bone metastases 4 months (IQR 82), median duration of prior BP therapy 14 months (IQR 19), and mean number of SREs/yr prior to entering study 0.35 (SD 0.76). Baseline median CTx was 120 ng/L (IQR 240) and BSAP 9.2 IU/L (IQR 3). To date: 26/71 pts (36%) remain on study. Reasons for coming off study include; study completion (18), elevation of CTx >600ng/L (10), or on study SRE (3). An elevation of CTx between baseline and wk 6 was significantly associated with coming off study early (p = 0.008). For pts who had had an SRE before study entry the odds ratios for coming off study early due to an on study SRE or elevated CTx was 1.005 (CI 1.002–1.009; p = 0.007) and for coming off early for an SRE was 0.0245 (CI 0.061–0.094; p = 0.046) respectively. Of the 8/13 pts who were ineligible due to baseline CTx >600ng/L, 6 had an SRE within 1 year of screening. Conclusion: De-escalating BP therapy to 12 weekly in low risk pts has advantages for both the pt and the health care system. Individual risk of SREs is highly variable, however baseline serum CTx levels Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-13-05.