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Poly(ADP-ribose) polymerase inhibitors (PARPis) have changed the treatment paradigm in breast cancer gene ( BRCA )-mutant high-grade serous ovarian carcinoma (HGSC). However, most patients eventually develop resistance to PARPis, highlighting an unmet need for improved therapeutic strategies. Using high-throughput drug screens, we identified ataxia telangiectasia and rad3-related protein/checkpoint kinase 1 (CHK1) pathway inhibitors as cytotoxic and further validated the activity of the CHK1 inhibitor (CHK1i) prexasertib in PARPi-sensitive and -resistant BRCA -mutant HGSC cells and xenograft mouse models. CHK1i monotherapy induced DNA damage, apoptosis, and tumor size reduction. We then conducted a phase 2 study (NCT02203513) of prexasertib in patients with BRCA -mutant HGSC. The treatment was well tolerated but yielded an objective response rate of 6% (1 of 17; one partial response) in patients with previous PARPi treatment. Exploratory biomarker analyses revealed that replication stress and fork stabilization were associated with clinical benefit to CHK1i. In particular, overexpression of Bloom syndrome RecQ helicase ( BLM ) and cyclin E1 ( CCNE1 ) overexpression or copy number gain/amplification were seen in patients who derived durable benefit from CHK1i. BRCA reversion mutation in previously PARPi-treated BRCA -mutant patients was not associated with resistance to CHK1i. Our findings suggest that replication fork-related genes should be further evaluated as biomarkers for CHK1i sensitivity in patients with BRCA -mutant HGSC.

Purpose: Breast and prostate cancer co-occur in families, and women with a family history of prostate cancer are at increased breast cancer risk. Prostate cancer is among the most heritable cancers, but few studies have investigated its association with familial breast cancer. The objective of this study is to investigate the extent to which familial breast or prostate cancer in first-degree relatives increases prostate cancer risk., Experimental Design: A prospective study of 37,002 U.S. men in the Health Professionals Follow-up Study. During the 16-year follow-up to 2012, 4,208 total and 344 lethal cases were diagnosed. Using cause-specific hazards regression, we estimated the multivariable HRs and 95% confidence intervals (CI) for associations between familial breast or prostate cancer and total and lethal prostate cancer., Results: Those with familial breast cancer had a 21% greater risk of prostate cancer overall (95% CI, 1.10-1.34), and a 34% greater risk of lethal disease (HR 1.34; 95% CI, 0.96-1.89). Family history of prostate cancer alone was associated with a 68% increased risk of total disease (95% CI, 1.53-1.83) and a 72% increased risk of lethal disease (95% CI, 1.25-2.38). Men with a family history of both cancers were also at elevated risk., Conclusions: Our study found that men with a family history of breast or prostate cancer had elevated prostate cancer risks, including risk of lethal disease. These findings have translational relevance for cancer risk prediction in men., (©2018 American Association for Cancer Research.)

Background: Breast cancer survivors with excess weight are more likely to have negative breast cancer outcomes. Biomarkers related to insulin resistance may help explain this negative association. Weight loss is associated with improvements in insulin sensitivity. Our goal was to identify the impact of a behaviorally based weight loss intervention on indices of insulin resistance., Methods: Overweight, early stage breast cancer survivors who completed initial cancer therapy were enrolled in a 6 month behaviorally based weight loss intervention that included calorie reduction, exercise and behavior modification. Biomarkers related to insulin resistance were obtained at baseline and after the intervention. Results from participants who achieved ≥5% weight loss were compared to those who lost less weight., Results: Despite not having diabetes as a preexisting diagnosis prior to the study, 69% of all participants were considered to have pre-diabetes or diabetes at baseline based on American Diabetes Association definitions. Participants who achieved ≥5% weight loss had significantly lower fasting insulin, AUC insulin, and insulin resistance as measured by HOMA-IR. Beta cell function decreased as anticipated when insulin resistance improved. Additionally, leptin levels declined., Conclusions: Breast cancer survivors who achieved ≥5% weight loss demonstrated significant improvements in indices of insulin resistance. Despite an exclusion criteria of diabetes at the time of enrolment, a high proportion met criteria for pre-diabetes or diabetes at baseline. Pre-diabetes appears to be under recognized in overweight breast cancer survivors. Behaviorally based weight loss interventions can result in weight loss and improvements in biomarkers related to breast cancer outcomes and additionally may decrease the chance of developing diabetes., Trial Registration: NCT01482702 4/12/2010 (retrospectively registered).  https://clinicaltrials.gov/ct2/show/NCT01482702?term=Dittus&rank=4.

Context: Screening reduces mortality from breast, cervical, and colorectal cancers. The Guide to Community Preventive Services previously conducted systematic reviews on the effectiveness of 11 interventions to increase screening for these cancers. This article presents results of updated systematic reviews for nine of these interventions., Evidence Acquisition: Five databases were searched for studies published during January 2004-October 2008. Studies had to (1) be a primary investigation of one or more intervention category; (2) be conducted in a country with a high-income economy; (3) provide information on at least one cancer screening outcome of interest; and (4) include screening use prior to intervention implementation or a concurrent group unexposed to the intervention category of interest. Forty-five studies were included in the reviews., Evidence Synthesis: Recommendations were added for one-on-one education to increase screening with fecal occult blood testing (FOBT) and group education to increase mammography screening. Strength of evidence for client reminder interventions to increase FOBT screening was upgraded from sufficient to strong. Previous findings and recommendations for reducing out-of-pocket costs (breast cancer screening); provider assessment and feedback (breast, cervical, and FOBT screening); one-on-one education and client reminders (breast and cervical cancer screening); and reducing structural barriers (breast cancer and FOBT screening) were reaffirmed or unchanged. Evidence remains insufficient to determine effectiveness for the remaining screening tests and intervention categories., Conclusions: Findings indicate new and reaffirmed interventions effective in promoting recommended cancer screening, including colorectal cancer screening. Findings can be used in community and healthcare settings to promote recommended care. Important research gaps also are described., (Published by Elsevier Inc.)

Previous studies have established that higher birthweight is associated with increased risk of breast cancer. However, the mechanisms underlying this association remain unclear. We explored whether maternal pregnancy weight gain and pre-pregnancy body mass index (BMI), which influence birthweight, are associated with risk of breast cancer in offspring. The Nurses' Mothers case-control study of breast cancer was nested in the Nurses' Health Study I and II cohorts. Mothers of 814 nurses with and 1,809 nurses without breast cancer completed questionnaires with information on pre-pregnancy height and weight, pregnancy weight gain, and other aspects of their pregnancies with the nurse daughters. We calculated odds ratios for breast cancer using conditional logistic regression. Mean pregnancy weight gain was 23 lb, and average pre-pregnancy BMI was 21 kg/m². Mothers' weight gain during pregnancy was not associated with the daughters' risk of breast cancer. Compared to women whose mothers gained 20-29 lb, women whose mothers gained less than 10 lb had a relative risk of 0.92 (95% confidence interval [CI]: 0.62-1.36), adjusting for the age of the nurses. Women whose mothers gained 40 or more pounds had a relative risk of 0.82 (95% CI: 0.55-1.23). Mothers' pre-pregnancy BMI was not associated with the daughters' risk of breast cancer. Women whose mothers had a pre-pregnancy BMI of 30 or more had a relative risk of 0.77 (95% CI: 0.34-1.74) compared to those with BMI less than 20. Additional adjustment for prenatal factors or for nurses' characteristics later in life had no effect on the results. The association between birthweight and breast cancer risk is likely due to factors independent of mothers' weight gain during pregnancy or pre-pregnancy BMI. Because BMIs and pregnancy weight gains were lower in this population than today, we cannot rule out associations for very high pre-pregnancy BMIs or pregnancy weight gains.

Background: Acrylamide is a probable human carcinogen formed during cooking of many common foods. Epidemiologic studies on acrylamide and breast cancer risk have been null; however, positive associations with ovarian and endometrial cancers have been reported. We studied acrylamide intake and risk for breast, endometrial, and ovarian cancers in a prospective cohort study., Methods: We assessed acrylamide intake among 88,672 women in the Nurses' Health Study using food frequency questionnaires administered every 4 years. Between 1980 and 2006, we identified 6,301 cases of invasive breast cancer, 484 cases of invasive endometrial adenocarcinoma, and 416 cases of epithelial ovarian cancer. We used Cox proportional hazards models to study the association between acrylamide and cancer risk., Results: We found no association between acrylamide intake and breast cancer overall or according to estrogen and progesterone receptor status. We found an increased risk for endometrial cancer among high acrylamide consumers (adjusted relative risk for highest versus lowest quintile = 1.41; 95% CI, 1.01-1.97; P for trend = 0.03). We observed a nonsignificant suggestion of increased risk for ovarian cancer overall (relative risk, 1.25; 95% CI, 0.88-1.77; P trend = 0.12), with a significantly increased risk for serous tumors (relative risk, 1.58; 95% CI, 0.99-2.52; P trend = 0.04). Associations did not differ by smoking status., Conclusions: We observed no association between acrylamide and breast cancer. Risk for endometrial cancer and possibly ovarian cancer was greater among high acrylamide consumers., Impact: This is the second prospective study to report positive associations with endometrial and ovarian cancers. These associations should be further evaluated to inform public health policy., (©2010 AACR.)

Acrylamide, a probable human carcinogen, is formed during high-temperature cooking of many commonly consumed foods. It is widespread; approximately 30% of calories consumed in the United States are from foods containing acrylamide. In animal studies, acrylamide causes mammary tumors, but it is unknown whether the level of acrylamide in foods affects human breast cancer risk. The authors studied the association between acrylamide intake and breast cancer risk among 90,628 premenopausal women in the Nurses' Health Study II. They calculated acrylamide intake from food frequency questionnaires in 1991, 1995, 1999, and 2003. From 1991 through 2005, they documented 1,179 cases of invasive breast cancer. They used Cox proportional hazards models to assess the association between acrylamide and breast cancer risk. The multivariable-adjusted relative risk of premenopausal breast cancer was 0.92 (95% confidence interval: 0.76, 1.11) for the highest versus the lowest quintile of acrylamide intake (P(trend) = 0.61). Results were similar regardless of smoking status or estrogen and progesterone receptor status of the tumors. The authors found no associations between intakes of foods high in acrylamide, including French fries, coffee, cereal, potato chips, potatoes, and baked goods, and breast cancer risk. They found no evidence that acrylamide intake, within the range of US diets, is associated with increased risk of premenopausal breast cancer.

This article provides an overview of behavioral and social science cancer screening intervention research and introduces the scope of topics addressed in this supplement to Cancer. The authors identify and address issues to consider before conducting interventions to promote the uptake of screening tests, such as the benefits and harms associated with screening. Trends in the use of cancer screening tests are discussed in the context of their efficacy and adoption over time. Both the development and breadth of social and behavioral intervention research intended to increase the use of effective tests are reviewed as background for the articles that follow. The application of the lessons from this extensive knowledge base not only should accelerate the uptake of the effective cancer screening tests currently available, but also can guide future directions for research.

This study examined the breast and cervical cancer screening practices of Hispanic and non-Hispanic women (n = 3,568) in counties that approximate the US southern border region. According to the Health Resources Services Administration (HRSA), border counties are those in which any part of the county is within 100 kilometers (62.14 miles) of the border. The study used data from Behavioral Risk Factor Surveillance System (BRFSS) surveys of adults aged > or = 18 years conducted in 1999 and 2000. The study looked at recent use of mammography and the Papanicolaou (Pap) test. Hispanic women were less likely to have had a recent mammogram or Pap test as compared with non-Hispanic women in border counties, and as compared with Hispanic and non-Hispanic women in nonborder counties of Texas, New Mexico, Arizona, and California combined, and with other women in the United States. Results underscore the need for continued efforts to ensure that medically underserved women who live in the border region have access to cancer screening services.

Women constitute about one in five hired farmworkers in the US. Their health may be affected by exposure to unhealthy living and working conditions, by increased exposure to health hazards, by poverty, and by poor utilization of health care and preventive services. About 69% of migrant and seasonal farmworkers were born outside the US, mostly in Mexico and central America, and many speak little English. The health concerns of women who are migrant and seasonal farmworkers include breast and cervical cancer, which can be prevented or controlled through routine screening, but cancer incidence and mortality data for migrant workers are sparse. We reviewed published studies that examined breast and cervical cancer screening in this population. These studies include cross-sectional surveys, health needs assessments, and randomized and non-randomized intervention trials. A review of published studies of cancer screening among women who are migrant and seasonal farmworkers indicates that underutilization of mammograms and Papanicolau (Pap) tests among this population may stem from their limited awareness of the importance of cancer screening and cultural beliefs. Other barriers include cost, lack of health insurance, lack of transportation and child care difficulties. The extent to which results obtained in selected localities are generalizable to other settings is uncertain, but results to date provide important information about possible approaches for increasing cancer screening among women migrant farmworkers.