A Randomized Phase II Study of MEDI0680 in Combination with Durvalumab versus Nivolumab Monotherapy in Patients with Advanced or Metastatic Clear-cell Renal Cell Carcinoma.

PURPOSE: MEDI0680 is a humanized anti-programmed cell death-1 (PD-1) antibody, and durvalumab is an anti-PD-L1 antibody. Combining treatment using these antibodies may improve efficacy versus blockade of PD-1 alone. This phase II study evaluated antitumor activity and safety of MEDI0680 plus durvalumab versus nivolumab monotherapy in immunotherapy-naïve patients with advanced clear-cell renal cell carcinoma who received at least one prior line of antiangiogenic therapy. PATIENTS AND METHODS: Patients received either MEDI0680 (20 mg/kg) with durvalumab (750 mg) or nivolumab (240 mg), all intravenous, every 2 weeks. The primary endpoint was investigator-assessed objective response rate (ORR). Secondary endpoints included best overall response, progression-free survival (PFS), safety, overall survival (OS), and immunogenicity. Exploratory endpoints included changes in circulating tumor DNA (ctDNA), baseline tumor mutational burden, and tumor-infiltrated immune cell profiles. RESULTS: Sixty-three patients were randomized (combination, n = 42; nivolumab, n = 21). ORR was 16.7% [7/42; 95% confidence interval (CI), 7.0-31.4] with combination treatment and 23.8% (5/21; 95% CI, 8.2-47.2) with nivolumab. Median PFS was 3.6 months in both arms; median OS was not reached in either arm. Because of adverse events, 23.8% of patients discontinued MEDI0680 and durvalumab and 14.3% of patients discontinued nivolumab. In the combination arm, reduction in ctDNA fraction was associated with longer PFS. ctDNA mutational analysis did not demonstrate an association with response in either arm. Tumor-infiltrated immune profiles showed an association between immune cell activation and response in the combination arm. CONCLUSIONS: MEDI0680 combined with durvalumab was safe and tolerable; however, it did not improve efficacy versus nivolumab monotherapy.

Pilot Study Assessing Tolerability and Metabolic Effects of Metformin in Patients With Li-Fraumeni Syndrome.

BACKGROUND: Li-Fraumeni syndrome (LFS) is a highly penetrant autosomal dominant cancer predisposition disorder caused by germline TP53 pathogenic variants. Patients with LFS have increased oxidative phosphorylation capacity in skeletal muscle and oxidative stress in blood. Metformin inhibits oxidative phosphorylation, reducing available energy for cancer cell proliferation and decreasing production of reactive oxygen species that cause DNA damage. Thus, metformin may provide pharmacologic risk reduction for cancer in patients with LFS, but its safety in nondiabetic patients with germline TP53 pathogenic variants has not been documented. METHODS: This study assessed safety and tolerability of metformin in nondiabetic LFS patients and measured changes in metabolic profiles. Adult patients with LFS and germline TP53 variant received 14 weeks of metformin. Blood samples were obtained for measurement of serum insulin-like growth factor-1, insulin, and insulin-like growth factor binding protein 3. Hepatic mitochondrial function was assessed with fasting exhaled CO2 after ingestion of 13C-labeled methionine. Changes in serum metabolome were measured. All statistical tests were 2-sided. RESULTS: We enrolled 26 participants: 20 females and 6 males. The most common adverse events were diarrhea (50.0%) and nausea (46.2%). Lactic acidosis did not occur, and there were no changes in fasting glucose. Cumulative mean 13C exhalation was statistically significantly suppressed by metformin (P = .001). Mean levels of insulin-like growth factor binding protein 3 and insulin-like growth factor-1 were statistically significantly lowered (P = .02). Lipid metabolites and branched-chain amino acids accumulated. CONCLUSIONS: Metformin was safe and tolerable in patients with LFS. It suppressed hepatic mitochondrial function as expected in these individuals. This study adds to the rationale for development of a pharmacologic risk-reduction clinical trial of metformin in LFS.

Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome.

Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder caused by germline mutations in TP53 that can lead to increased mitochondrial metabolism in patients. However, the implications of altered mitochondrial function for tumorigenesis in LFS are unclear. Here, we have reported that genetic or pharmacologic disruption of mitochondrial respiration improves cancer-free survival in a mouse model of LFS that expresses mutant p53. Mechanistically, inhibition of mitochondrial function increased autophagy and decreased the aberrant proliferation signaling caused by mutant p53. In a pilot study, LFS patients treated with metformin exhibited decreases in mitochondrial activity concomitant with activation of antiproliferation signaling, thus reproducing the effects of disrupting mitochondrial function observed in LFS mice. These observations indicate that a commonly prescribed diabetic medicine can restrain mitochondrial metabolism and tumorigenesis in an LFS model, supporting its further consideration for cancer prevention in LFS patients.

Hereditary cancer syndromes as model systems for chemopreventive agent development.

Research in chemoprevention has undergone a shift in emphasis for pragmatic reasons from large, phase III randomized studies to earlier phase studies focused on safety, mechanisms, and utilization of surrogate endpoints such as biomarkers instead of cancer incidence. This transition permits trials to be conducted in smaller populations and at substantially reduced costs while still yielding valuable information. This article will summarize some of the current chemoprevention challenges and the justification for the use of animal models to facilitate identification and testing of chemopreventive agents as illustrated though four inherited cancer syndromes. Preclinical models of inherited cancer syndromes serve as prototypical systems in which chemopreventive agents can be developed for ultimate application to both the sporadic and inherited cancer settings.

Symptoms and QOL as Predictors of Chemoprevention Adherence in NRG Oncology/NSABP Trial P-1.

BACKGROUND: Tamoxifen provides a 50% reduction in the incidence of breast cancer (BC) among high-risk women, yet many do not adhere to the five-year course of therapy. Using the prospective double-blind National Surgical Adjuvant Breast and Bowel Project P-1 study, we evaluated whether participant-reported outcomes were associated with drug adherence and whether baseline behavioral risk factors modified those associations. METHODS: P-1 participants were randomly assigned to placebo vs tamoxifen (20mg/day). Mixed effects logistic regression was used to evaluate whether baseline or three-month SF-36 quality of life (QOL) mental and physical component summaries (MCS, PCS), and participant-reported symptoms (gynecologic, vasomotor, sexual, and other) predicted 12-month drug adherence (76-100% of assigned medication). The evaluation accounted for age, treatment, estimated breast cancer risk, education, baseline smoking, alcohol consumption, and obesity. All statistical tests were two-sided. RESULTS: Participants enrolled at least three years before trial unblinding and without medically indicated discontinuation before 12 months were eligible for the present analyses (n = 10 576). At 12 months, 84.3% were adherent. Statistically significant predictors of adherence were: three-month MCS (odds ratio [OR] = 1.15 per 10 points, 95% confidence interval [CI] = 1.06 to 1.25); three-month gynecologic symptoms among moderate alcohol drinkers (OR = .79, 95% CI = 0.72 to 0.88); baseline vasomotor symptoms among participants assigned tamoxifen (OR = .88, 95% CI = 0.80 to 0.97); and three-month sexual symptoms among younger participants (OR = .89 at age 41 years, 95% CI = 0.80 to 0.99). The strongest association was with three-month other symptoms (OR = .77, 95% CI = 0.63 to 0.93). PCS was not associated with adherence. Symptom and QOL associations were not modified by smoking or obesity. CONCLUSIONS: Promoting QOL and managing symptoms early in therapy may be important strategies to improve adherence.

The Affordable Care Act and genetic testing for inheritable cancer syndromes: impact on high-risk underserved minorities.

Genetic testing for inheritable cancer syndromes is becoming a critical part of preventive health services. The Patient Protection and Affordable Care Act (PPACA) Essential Health Benefits package addresses breast cancer susceptibility-gene testing for women who are unaffected by cancer. The absence of provisions for 1) men, 2) cancer patients, 3) other inheritable cancer syndromes, and 4) risk-reducing interventions are limitations of PPACA. We discuss provisions and limitations of PPACA pertaining to genetic testing and effects on high-risk populations, in particular minorities. The PPACA is the beginning of an ongoing process of incorporating genetic testing in the armamentarium of cancer prevention. Future efforts should focus on ensuring equitable access to genetic testing as a preventive service under PPACA to high-risk populations other than women. Consideration should also be given to provisions for risk-reducing interventions, especially in underserved minority populations, who are known to underutilize genetic testing and may have limited financial resources for medical intervention.

Genetic and environmental determinants on tissue response to in vitro carcinogen exposure and risk of breast cancer.

To test the hypothesis that individual susceptibility to carcinogen exposure is a risk factor for breast cancer, we measured DNA adduct formation in normal breast tissues treated in vitro with 4 micro M benzo(a)pyrene in 76 cancer cases and 60 noncancer controls. We found a significantly higher level of adducts (134.6 +/- 21.2/10(9)) among cases compared with controls (66.9 +/- 7.5; P = 0.007). The level of adducts was significantly associated with the risk of breast cancer (odds ratio, 4.38; 95% confidence interval, 1.04 to 18.50; P = 0.044) after adjusting for confounders. Stratified analysis and regression analysis demonstrated that race, pack-years of smoking, family history of breast cancer, and CYP1B1 genotype were significant predictors of the level of benzo(a)pyrene-induced adducts in the breast tissues. These observations suggest that genetic susceptibility to carcinogen exposure may play an important role in breast carcinogenesis.

A case-control study of dietary phytoestrogens and testicular cancer risk.

A few dietary studies have found elevated testicular cancer risks for higher red meat, fat, and milk intakes and lower intakes of fruits, vegetables, and fiber. Because hormonal modulation by dietary intake of plant estrogens could affect risk of testicular cancer, we chose to explore the possible relationship between dietary phytoestrogens and testicular cancer. We conducted a hospital-based case-control study of 159 testicular cancer cases diagnosed between 1990 and 1996 and 136 adult friend-matched controls at the University of Texas M. D. Anderson Cancer Center. Amounts of phytoestrogenic compounds in foods were added to the National Cancer Institute's DietSys program and then grouped into prelignans, lignans, flavonoids, isoflavonoids, phytosterols, and coumestrol for statistical analysis, expressed per 1,000 kcal. The results of multivariate logistic regression analysis showed, after adjustment for age, education, income, ethnicity, cryptorchidism, body mass index, baldness unrelated to therapy, severe acne in adolescence, early puberty, daily fiber and fat intake, and total daily calories, no discernable monotonic increased or decreased risk estimates across quartiles of phytoestrogen intake. A U-shaped pattern was observed for lignans and coumestrol. Further evaluation of this pattern by cubic spline parameterization did fit the data, but the data were also consistent with no effect. This hypothesis-generating study does not support the premise that dietary phytoestrogens increase or decrease testicular cancer risk in young men.