CANCER RISK

Effect of Time of Day of Recreational and Household Physical Activity on Prostate and Breast Cancer Risk (MCC Spain Study)

One potential cause of cancer is circadian disruption, the misalignment of environmental cues (light, food intake, etc.) and our endogenous circadian rhythms. It is established that regular physical activity throughout a lifetime can reduce cancer risk. A recent study showed that physical activity done in the morning can be most beneficial to reducing cancer risk (Int J Cancer 2020; https://doi.org/10.1002/ijc.33310). To date, it remains unknown if the timing of physical activity could influence cancer risk through circadian disruption. To address this question, the researchers examined the effect of timing of recreational physical activity on breast and prostate cancer risk in a population-based case control study. They hypothesized that the beneficial effect of the longest done physical activity in reducing cancer risk could be stronger when done in the morning. They based their hypothesis on the results of an experimental study which showed that physical activity in the afternoon and in the evening can delay melatonin production, a hormone produced mainly during the night and with well-known oncostatic properties. The analysis included 2,795 participants of the multicase-control (MCC-Spain) study in Spain. The researchers found that the beneficial effect of the physical activity (longest done throughout lifetime) to reduce breast and prostate cancer risk was stronger when the activity was regularly done in the morning (8-10 am). In men, the effect was similarly strong also for evening activity (7-11 pm). Results were unchanged when considering the most strenuous physical activity timing. Effects differed across chronotypes, the preference for sleeping and being active at a certain time of day. Early morning activity (8-10 am) seemed especially protective for late chronotypes, people who generally prefer to be active towards the evening. In their paper, the epidemiologists discuss how physical activity may influence human circadian rhythms and suggest possible biological mechanisms (e.g., alteration of melatonin and sex hormone production, nutrient metabolism, etc.). Overall, the findings of this study indicate that "time of the day of physical activity is an important aspect that may potentiate the protective effect of physical activity on cancer risk."

SMOKING CESSATION

Effect of Sustained Smoking Cessation Counseling and Provision of Medication vs Shorter-Term Counseling and Medication Advice on Smoking Abstinence in Patients Recently Diagnosed With Cancer

Recently diagnosed cancer patients who smoke are significantly more likely to quit and remain tobacco-free if they receive frequent and sustained telephone counseling, according to a new study (JAMA 2020; doi: 10.1001/jama.2020.14581). The study offers hope that these patients will respond better to treatment and enjoy improved quality of life while coping with cancer. The study included 303 patients with various forms of cancer. Half of the participants received phone calls from counselors 4 times a week for a month. During these sessions, counselors used evidence-based behavioral strategies designed to motivate the patient to continue abstaining from tobacco and cope with the stress of a cancer diagnosis. Patients also received advice about medications to aid smoking cessation, such as nicotine-replacement therapy. The intensive-treatment group received a similar schedule of telephone counseling, plus an additional four sessions every other week for 2 months, and three monthly booster sessions. Patients in this group were also offered free smoking-cessation medications. After 6 months, lab tests confirmed that 34.5 percent of the patients in the intensive-treatment program were abstaining from tobacco, compared to 21.5 percent of participants who received the shorter program with less frequent counseling.

UROTHELIAL CARCINOMA

Neoadjuvant PD-L1 Plus CTLA-4 Blockade in Patients With Cisplatin-Ineligible Operable High-Risk Urothelial Carcinoma

Neoadjuvant combination treatment with the immune checkpoint inhibitors tremelimumab (anti-CTLA-4) and durvalumab (anti-PD-1) was well-tolerated and showed early signs of activity in certain patients with localized bladder cancer who do not have standard treatment options available, according to a Phase I clinical trial (Nat Med 2020; https://doi.org/10.1038/s41591-020-1086-y). This represents the first neoadjuvant trial of combination immunotherapy for bladder cancer patients ineligible to receive cisplatin-based chemotherapy, all of whom had tumors with high-risk features that are associated with unfavorable outcomes. Of the 28 cisplatin-ineligible patients with high-risk localized bladder cancer enrolled in the trial, 24 completed bladder removal surgery on the study with nine (37.5%) achieving a pathologic complete response (pCR). Additionally, in 12 patients with particularly large tumors (stage T3-T4), the pCR rate was 42 percent, and half saw their tumor size reduced to stage T1 or less. Each patient received two doses of durvalumab and tremelimumab in combination and 24 patients completed surgery following treatment. Trial participants were 82 percent Caucasian and 18 percent Black or other races. Median age was 71 with men accounting for 71 percent and women 29 percent of participants. Most patients experienced immune-related side effects, the most common of which were grade 1-2 rash (29%) and asymptomatic increases in amylase (29%). Six patients (21%) experienced grade 3 or higher immune-related adverse events, including asymptomatic laboratory values, hepatitis, and colitis. No treatment-related deaths occurred. Median overall survival has not been reached, and 24 patients were still alive at 1 year. In addition, 82.8 percent of patients that had surgery were free of disease recurrence at 1 year. The researchers also collected pre- and post-treatment blood and tissue samples from patients to study biomarkers associated with response in collaboration with MD Anderson's immunotherapy platform. The researchers identified a higher density of specialized immune-cell clusters called tertiary lymphoid structures (TLS) in pre-treatment tumor samples from patients who responded well to combination therapy relative to those who did not respond. A higher density of TLS correlated with longer overall survival and relapse-free survival.

RETINOBLASTOMA

GD2-Specific CAR T Cells Encapsulated in an Injectable Hydrogel Control Retinoblastoma and Preserve Vision

A treatment that uses immune system T cells, combined with an immune-boosting drug packaged in an injectable gel, was found to preserve the vision of mice implanted with retinoblastoma tissue (Nat Cancer 2020; https://doi.org/10.1038/s43018-020-00119-y). The cancer is treatable in early stages, but can still lead to the loss of vision in about 5 percent of cases. The researchers used an incremental process to determine the best method for treatment of retinoblastoma. First, the researchers turned to chimeric antigen receptor-T (CAR-T) cell therapy, a type of immunotherapy where T cells that comprise the immune system are modified in the laboratory to express chimeric antigen receptors (CARs) that target surface proteins on cancer cells. In a lab test, they found that a molecule, GD2, is expressed in retinoblastoma but the possibility to target this molecule to safely eliminate the tumor in the eye was unknown. Next, to test the safety and benefit of targeting GD2, the investigators injected the CAR-T that recognizes this molecule into the retina of mice implanted with retinoblastoma cancer cells and found the therapy delayed tumor development but did not eradicate the tumor. Then they combined the CAR-Ts with interleukin (IL)-15, a protein that can boost immune response, and found that 60 percent of mice were tumor-free for up to 70 days. Finally, they injected a water-based gel containing the CAR-Ts and IL-15 into the retinas of the mice. The CAR-Ts and IL-15 retained an extended ability to attack the cancer cells, control tumor growth, and prevent tumor recurrence. They corroborated the lack of tumor growth with several imaging exams of the retina. This gel-encapsulated therapy is currently being tested in clinical trials in children with neuroblastoma, an embryonal tumor that can progress rapidly and has some of the same genetic characteristics of retinoblastoma.