Racial differences in familiarity, interest, and use of integrative medicine among patients with breast cancer.

Purpose Integrative medicine (IM) has received ASCO endorsement for managing cancer treatment-related side effects. Little is known about racial differences in familiarity, interest, and use of IM among breast cancer patients. Methods Breast cancer patients enrolled in the Chicago Multiethnic Epidemiologic Breast Cancer Cohort were surveyed regarding familiarity, interest, and use of IM: acupuncture, massage, meditation, music therapy, and yoga. Familiarity and interest, measured by a 5-point Likert scale, was modeled using proportional odds. Use was self-reported, modeled using binary logistic regression. Results Of 1,300 respondents (71.4% White and 21.9% Black), Black patients were less likely than White patients to be familiar with acupuncture (aOR 0.60, 95% CI: 0.41-0.87). While there was no differences in interest in acupuncture between Black and White patients (aOR 1.12, 95% CI: 0.76-1.65), Black patients were more interested in massage (aOR 1.86, 95% CI: 1.25-2.77), meditation (aOR 2.03, 95% CI: 1.37-3.00), music therapy (aOR 2.68, 95% CI: 1.80-3.99) and yoga (aOR 2.10, 95% CI: 1.41-3.12). Black patients were less likely than White to have used acupuncture (aOR 0.49, 95% CI: 0.29-0.84); but there were no racial differences in use of massage (aOR 0.83, 95% CI: 0.53-1.30), meditation (aOR 0.82, 95% CI: 0.47-1.43), music therapy (aOR 1.65, 95% CI: 0.82-3.32) and yoga (aOR 0.67, 95% CI: 0.37-1.20). Conclusion Black patients expressed more interest in IM than their White counterparts; there were no racial differences in IM use, except lower acupuncture use among Black patients. A breast program focused on equity should provide access to these services for breast cancer patients.

Unawareness of breast cancer family history among African women.

Introduction: comprehensive cancer risk assessment services are lacking in most sub-Saharan African countries and the use of accurate family history (FH) information could serve as a cheap strategy for risk evaluation. The aim of this study is to determine the proportion of women unaware of family history of cancer among female relatives and associated socio-demographic characteristics. Methods: using case-control data on breast cancer among 4294 women in Nigeria, Uganda and Cameroon, we investigated the proportion of women unaware of family history of cancer among their female relatives. The association between participants' response to their awareness of female relatives' cancer history and socio-demographic characteristics was analysed according to case-control status, family side and distance of relation. Results: the proportion of women unaware if any relative had cancer was 33%, and was significantly higher among controls (43.2%) compared to 23.9% among cases (p<0.001) (Adjusted Odds Ratio (OR) = 2.51, 95% CI = 2.14 - 2.95). Age, education and marital status remained significantly associated with being unaware of FH among controls on multiple regression. Conclusion: about a third of women interviewed did not know about cancer history in at least one of their female relatives. Efforts aimed at improving cancer awareness in sub-Saharan Africa (SSA) are needed. Our findings could be useful for future studies of cancer risk assessment in SSA.

PTPN2 copper-sensing rapidly relays copper level fluctuations into EGFR/CREB activation and associated CTR1 transcriptional repression.

Fluxes in human intra- and extracellular copper levels recently garnered attention for roles in cellular signaling, including affecting levels of the signaling molecule cyclic adenosine monophosphate (cAMP). We herein applied an unbiased temporal evaluation of the whole-genome transcriptional activities modulated by fluctuations in copper levels to identify the copper sensor proteins responsible for driving these activities. We found that fluctuations in physiologically-relevant copper levels rapidly modulate EGFR/MAPK/ERK signal transduction and activation of the transcription factor cAMP response element-binding protein (CREB). Both intracellular and extracellular assays support Cu 1+ inhibition of the EGFR-phosphatase PTPN2 (and potentially the homologous PTPN1)-via direct ligation to the PTPN2 active site cysteine side chain-as the underlying mechanism of copper-stimulated EGFR signal transduction activation. Depletion of copper represses this signaling pathway. We additionally show i ) copper supplementation drives transcriptional repression of the copper importer CTR1 and ii ) CREB activity is inversely correlated with CTR1 expression. In summary, our study reveals PTPN2 as a physiological copper sensor and defines a regulatory mechanism linking feedback control of copper-stimulated MAPK/ERK/CREB-signaling and CTR1 expression, thereby uncovering a previously unrecognized link between copper levels and cellular signal transduction.

Demographic and Clinical Characteristics Associated With Familiarity, Interest, and Use of Integrative Therapies Among Patients With Breast Cancer.

BACKGROUND: Integrative therapies reduce side effects from cancer treatment, though remain underutilized. There is a paucity of data on factors associated with familiarity, interest, and use of these therapies among breast cancer patients. METHODS: A survey on familiarity, interest, and use of acupuncture, massage, meditation, music therapy, and yoga was conducted in patients enrolled in the Chicago Multiethnic Epidemiologic Breast Cancer Cohort. Familiarity and interest were assessed using a five-point Likert scale, and modeled using proportional odds regression. Use was per self-report, modeled using logistic regression. Adjusted odds ratios (aOR) and 95% confidence intervals (95% CI) were calculated. RESULTS: Of 1300 study participants, 59.6% were familiar with massage, 47.2% acupuncture, 46.9% meditation, 46.5% yoga, and 34.5% music therapy; 63.3% were interested in massage, 50.2% yoga, 47.9% meditation, 44.2% acupuncture, and 41.4% music therapy. Only 41.3% had used massage, 25.8% acupuncture, 18.7% yoga, 18.5% meditation, and 7.4% music therapy. Older age and lower education level were associated with lower familiarity and interest. Black patients were more likely than White patients to be interested. Patients' interest increased significantly when certain symptoms were treated. In the adjusted models, patients ages 40 to 65 were less likely than those ages <40 to have used massage (aOR 0.55, 95% CI: 0.31-0.98), yoga (aOR 0.52, 95% CI: 0.27-0.99), or meditation (aOR 0.47, 95% CI: 0.25-0.90). Patients with high school education were less likely than those with a graduate degree to have used acupuncture (aOR 0.42, 95% CI: 0.24-0.72), massage (aOR 0.39, 95% CI: 0.25-0.62), or meditation (aOR 0.26, 95% CI: 0.12-0.58). Having received chemotherapy was associated with increased interest in yoga (aOR 1.36, 95% CI: 1.07-1.73), massage (aOR 1.27, 95% CI: 1.01-1.59), or meditation (aOR 1.26, 95% CI: 1.01-1.57). Receipt of hormone therapy was not associated with interest or use. CONCLUSION: In this racially diverse cohort of patients, familiarity and interest of integrative therapies were high, while use was low. Older age and lower education level were associated with lack of interest and use. Chemotherapy was associated with interest, but hormone therapy was not. Strategies to promote the benefits and use of integrative therapies among breast cancer patients are needed.

Mutational spectrum of breast cancer susceptibility genes among women ascertained in a cancer risk clinic in Northeast Brazil.

PURPOSE: There is a paucity of data on the spectrum and prevalence of pathogenic variants among women of African ancestry in the Northeast region of Brazil. METHODS: We performed BROCA panel sequencing to identify inherited loss-of-function variants in breast cancer susceptibility genes among 292 Brazilian women referred to a single institution cancer risk assessment program. RESULTS: The study included a convenient cohort of 173 women with invasive breast cancer (cases) and 119 women who were cancer-free at the time of ascertainment. The majority of the women self-reported as African-descended (67% for cases and 90.8% for unaffected volunteers). Thirty-seven pathogenic variants were found in 36 (20.8%) patients. While the spectrum of pathogenic variants was heterogeneous, the majority (70.3%) of the pathogenic variants were detected in high-risk genes BRCA1, BRCA2, PALB2, and TP53. Pathogenic variants were also found in the ATM, BARD1, BRIP1, FAM175A, FANCM, NBN, and SLX4 genes in 6.4% of the affected women. Four recurrent pathogenic variants were detected in 11 patients of African ancestry. Only one unaffected woman had a pathogenic variant in the RAD51C gene. Different risk assessment models examined performed well in predicting risk of carrying germline loss-of-function variants in BRCA1 and/or BRCA2 in breast cancer cases. CONCLUSION: The high prevalence and heterogenous spectrum of pathogenic variants identified among self-reported African descendants in Northeast Brazil is consistent with studies in other African ancestry populations with a high burden of aggressive young onset breast cancer. It underscores the need to integrate comprehensive cancer risk assessment and genomic testing in the management of newly diagnosed Black women with breast cancer across the African Diaspora, enabling improved cancer control in admixed underserved and understudied populations.

Prevalence of potential interactions of medications, including herbs and supplements, before, during, and after chemotherapy in patients with breast and prostate cancer.

BACKGROUND: The use of herbs and supplements (HS) is common among patients with cancer, yet limited information exists about potential medication interactions (PMIs) with HS use around chemotherapy. METHODS: Patients with breast or prostate cancer who had recently finished chemotherapy at 2 academic medical centers were surveyed by telephone. Interviewers inquired about all medications, including HS, before, during, and after chemotherapy. Micromedex, Lexicomp, and Natural Medicines Comprehensive Database interaction software programs were used to determine PMIs. RESULTS: A total of 67 subjects (age range, 39-77 years) were evaluated in this study. Participants were primarily White patients (73%) with breast cancer (87%). The median number of medications was 11 (range, 2-28) during the entire study and was highest during chemotherapy (7; range, 2-22). Approximately four-fifths (84%) used HS. A total of 1747 PMIs were identified, and they represented 635 unique PMIs across all 3 timeframes, with most occurring during chemotherapy. Prescription-related PMIs (70%) were the most common type, and they were followed by HS-related (56%) and anticancer treatment-related PMIs (22%). Approximately half of the PMIs (54%) were categorized as moderate interactions, and more than one-third (38%) were categorized as major interactions. Patient use of HS increased from 51% during chemotherapy to 66% after chemotherapy, and this correlated with an increased prevalence of HS PMIs (46% to 60%). HS users were more likely to be at risk for a major PMI than non-HS users (92% vs 70%; P = .038). CONCLUSIONS: The use of HS remains prevalent among patients with cancer and may place them at risk for PMIs both during chemotherapy and after the completion of treatment. LAY SUMMARY: This study evaluates the risk of potential medication interactions for patients with breast or prostate cancer undergoing chemotherapy. The results show that patients often use herbs and supplements during treatment. Prescription medications are most often associated with medication interactions, which are followed by herb and supplement-related interactions. More than one-third of potential medication interactions are considered major. Patients should be educated about the risk of herb and supplement-related medication interactions during treatment.

Racial disparities in survival outcomes among breast cancer patients by molecular subtypes.

PURPOSE: Differences in tumor biology, genomic architecture, and health care delivery patterns contribute to the breast cancer mortality gap between White and Black patients in the US. Although this gap has been well documented in previous literature, it remains uncertain how large the actual effect size of race is for different survival outcomes and the four breast cancer subtypes. METHODS: We established a breast cancer patient cohort at the University of Chicago Comprehensive Cancer Center. We chose five major survival outcomes to study: overall survival, recurrence-free survival, breast-cancer-specific survival, time-to-recurrence and post-recurrence survival. Cox proportional hazards models were used to estimate the hazard ratios between Black and White patients, adjusting for selected patient, tumor, and treatment characteristics, and also stratified by the four breast cancer subtypes. RESULTS: The study included 2795 stage I-III breast cancer patients (54% White and 38% Black). After adjusting for selected patient, tumor and treatment characteristics, Black patients still did worse than White patients in all five survival outcomes. The racial difference was highest within the HR-/HER2+ subgroup, in both overall survival (hazard ratio = 4.00, 95% CI 1.47-10.86) and recurrence-free survival (hazard ratio = 3.00, 95% CI 1.36-6.60), adjusting for age at diagnosis, cancer stage, and comorbidities. There was also a significant racial disparity within the HR+/HER2- group in both overall survival and recurrence-free survival. CONCLUSIONS: Our study confirmed that racial disparity existed between White and Black breast cancer patients in terms of both survival and recurrence, and found that this disparity was largest among HR-/HER2+ and HR+/HER2- patients.

The Influence of Spirituality and Religiosity on US Oncologists' Personal Use of and Clinical Practices Regarding Complementary and Alternative Medicine.

BACKGROUND: Cancer patients frequently use complementary and alternative medicine (CAM), and spirituality has been associated with CAM use among patients. We evaluated how oncologists' spirituality and religiosity are associated with personal use and patient recommendations for CAM. METHODS: A survey was mailed to 1000 medical oncologists in the United States. The questionnaire asked about oncologists' approaches to CAM use by patients, focusing on the use of herbs and supplement (HS), and about religiosity and spirituality. RESULTS: Of 937 deliverable questionnaires, 392 were returned (response rate 42%). Respondents were mostly men (71%) and Caucasian (76%), with a median age of 48. Approximately 16% reported no religion, 19% Jewish, 24% Catholic, 28% Christian, and 13% other religions. Eighteen percent reported attending religious services at least once a week, including 15% who attend several times per week. Twenty-eight percent reported high theological pluralism (skepticism regarding whether one religion is comprehensively and uniquely true); 58% described themselves as moderately or very spiritual. Self-reported spirituality and religious service attendance were associated with using CAM personally and recommending HS to patients. In multivariate analyses, moderate-high spirituality and attending religious services less than monthly was positively associated with personal use of CAM: odds ratio (OR) = 3.10 (confidence interval [CI] = 1.5-6.5) and OR = 3.04 (CI = 1.5-6.6), respectively. Physicians with moderate to high spirituality were more likely to report recommending CAM in general (OR = 3.07, CI = 1.3-7.1), but less likely to report recommending HS (OR = 0.33, CI = 0.14-0.75). CONCLUSION: Self-reported spirituality is a significant factor among US oncologists' decision to use CAM and recommend CAM to patients.

Implementing newborn screening for sickle cell disease as part of immunisation programmes in Nigeria: a feasibility study.

BACKGROUND: Sickle cell disease is highly prevalent in sub-Saharan Africa, where it accounts for substantial morbidity and mortality. Newborn screening is paramount for early diagnosis and enrolment of affected children into a comprehensive care programme. Up to now, this strategy has been greatly impaired in resource-poor countries, because screening methods are technologically and financially intensive; affordable, reliable, and accurate methods are needed. We aimed to test the feasibility of implementing a sickle cell disease screening programme using innovative point-of-care test devices into existing immunisation programmes in primary health-care settings. METHODS: Building on a routine immunisation programme and using existing facilities and staff, we did a prospective feasibility study at five primary health-care centres within Gwagwalada Area Council, Abuja, Nigeria. We systematically screened for sickle cell disease consecutive newborn babies and infants younger than 9 months who presented to immunisation clinics at these five centres, using an ELISA-based point-of care test (HemoTypeSC). A subgroup of consecutive babies who presented to immunisation clinics at the primary health-care centres, whose mothers gave consent, were tested by the HemoTypeSC point-of-care test alongside a different immunoassay-based point-of-care test (SickleSCAN) and the gold standard test, high-performance liquid chromatography (HPLC). FINDINGS: Between July 14, 2017, and Sept 3, 2019, 3603 newborn babies and infants who presented for immunisation were screened for sickle cell disease at five primary health-care centres using the ELISA-based point-of-care test. We identified 51 (1%) children with sickle cell anaemia (HbSS), four (<1%) heterozygous for HbS and HbC (HbSC), 740 (21%) with sickle cell trait (HbAS), 34 (1%) heterozygous for HbA and HbC (HbAC), and 2774 (77%) with normal haemoglobin (HbAA). Of the 55 babies and infants with confirmed sickle cell disease, 41 (75%) were enrolled into a programme for free folic acid and penicillin, of whom 36 (88%) completed three visits over 9 months (median follow-up 226 days [IQR 198-357]). The head-to-head comparison between the two point-of-care tests and HPLC showed concordance between the three testing methods in screening 313 newborn babies, with a specificity of 100% with HemoTypeSC, 100% with SickleSCAN, and 100% by HPLC, and a sensitivity of 100% with HemoTypeSC, 100% with SickleSCAN, and 100% by HPLC. INTERPRETATION: Our pilot study shows that the integration of newborn screening into existing primary health-care immunisation programmes is feasible and can rapidly be implemented with limited resources. Point-of-care tests are reliable and accurate in newborn screening for sickle cell disease. This feasibility study bodes well for the care of patients with sickle cell disease in resource-poor countries. FUNDING: Doris Duke Charitable Foundation, Imperial College London Wellcome Trust Centre for Global Health Research, and Richard and Susan Kiphart Family Foundation.

Utilization of Complementary Alternative Medicine, Diet, and Exercise Among Women at High Risk for Developing Breast Cancer.

Background: Women diagnosed as having a high risk for breast cancer (HR-BC) often seek different health behaviors (HBs) such as complementary and alternative medicine (CAM), diet, and exercise to improve their health and cancer outcome. Methods: Women already enrolled in a multimodality screening study for patients at HR-BC (gene mutation carrier or >20% cumulative lifetime risk) were given a questionnaire to evaluate their use of CAM therapies, diet, and exercise before and after a diagnosis of HR-BC. Patients were also asked to complete the Short-Form 36, State-Trait Anxiety Inventory, and Beck Depression Inventory. Results: A total of 134 (67%) subjects completed the survey from the original cohort. General characteristics included a median age of 46 years (range = 24-73 years), majority were White (91%), BRCA1/2 gene mutation carrier (49%), and prior diagnosis of breast and/or ovarian cancer (30%). Almost all of the patients reported a lifetime prevalence of any HB (97%) and CAM utilization (91%). Subjects also had a high lifetime utilization of exercise (83%), herbs and supplements(72%), and diet programs (58%). All of these HBs declined in utilization after diagnosis of HR-BC by as much as 30%. After diagnosis of a HR-BC, a personal history of breast and/or ovarian cancer was significantly correlated with increased use of CAM (odds ratio [OR] = 5.9, P < .01), herbs and supplements (OR = 4.3, P < .01), and diet program (OR = 4.4, P < .01) in multivariate analysis. Conclusions: HBs such as CAM, diet, and exercise are highly prevalent among women with HR-BC, and the utilization of HB decreases significantly after diagnosis of HR-BC.

Traditional medicine usage among adult women in Ibadan, Nigeria: a cross-sectional study.

BACKGROUND: Previous research has revealed high rates of traditional medicine usage in Nigeria. Reports of widespread contamination of herbal medicine products and higher rates of noncompliance with Western medications among traditional medicine users have raised concerns about the safety of traditional medicine use. Few studies have explored how demographic factors predict rates of traditional medicine use in the general population. METHODS: We conducted interviews of 748 adult women recruited from the communities in the city of Ibadan, Nigeria from 2013 to 2015. A structured questionnaire was created to collect data on rates of traditional medicine use and demographic factors such as age, education, ethnicity, and occupation. Multivariate logistic regressions were run to examine factors related to traditional medicine use, and the effects were measured with odds ratios (OR) along with 95% confidence interval (95%CI). RESULTS: The overall proportion of traditional medicine use was 81.6%. Women from the Ibo and Hausa ethnic groups were significantly less likely to use traditional medicine than the majority Yoruba group (OR 0.25, 95%CI 0.10-0.63;, OR 0.43, 95%CI 0.24-0.76) respectively). In addition, educated women were less likely than their non-educated counterparts to have used traditional medicine, with the biggest effect seen in women with a secondary education (OR 0.42, 95%CI 0.21-0.85). CONCLUSIONS: We found a high rate of traditional medicine usage, consistent with that found in prior research. A novel finding was the significance of ethnicity as a predictor for usage rates.

Clinical interpretation of pathogenic ATM and CHEK2 variants on multigene panel tests: navigating moderate risk.

Comprehensive genomic cancer risk assessment (GCRA) helps patients, family members, and providers make informed choices about cancer screening, surgical and chemotherapeutic risk reduction, and genetically targeted cancer therapies. The increasing availability of multigene panel tests for clinical applications allows testing of well-defined high-risk genes, as well as moderate-risk genes, for which the penetrance and spectrum of cancer risk are less well characterized. Moderate-risk genes are defined as genes that, when altered by a pathogenic variant, confer a 2 to fivefold relative risk of cancer. Two such genes included on many comprehensive cancer panels are the DNA repair genes ATM and CHEK2, best known for moderately increased risk of breast cancer development. However, the impact of screening and preventative interventions and spectrum of cancer risk beyond breast cancer associated with ATM and/or CHEK2 variants remain less well characterized. We convened a large, multidisciplinary, cross-sectional panel of GCRA clinicians to review challenging, peer-submitted cases of patients identified with ATM or CHEK2 variants. This paper summarizes the inter-professional case discussion and recommendations generated during the session, the level of concordance with respect to recommendations between the academic and community clinician participants for each case, and potential barriers to implementing recommended care in various practice settings.

Mutations in context: implications of BRCA testing in diverse populations.

Cancer is a common non-communicable disease worldwide, although it exhibits differential population trends in incidence and mortality rates. The differences relate to population structure, environmental risk factors as well as health system organization. This article discusses the potential impact of genetic testing on population health, focusing in particular on the mutational spectrum of breast cancer susceptibility genes in diverse populations. We identify the need for improved access to, and increased investment in, comprehensive cancer risk assessment and genetic testing as well as cancer control measures that take into account lifestyle, environmental, and social factors in understudied minority groups.

National survey of US oncologists' knowledge, attitudes, and practice patterns regarding herb and supplement use by patients with cancer.

PURPOSE: Patients with cancer commonly use complementary and alternative medicine, including herbs and supplements (HS), during cancer treatment. This national survey explored oncologists' knowledge, attitudes, and practice patterns regarding HS use by their patients. METHODS: A survey was sent by mail and e-mail to a random sample of 1,000 members of the American Society for Clinical Oncology. The questions covered several topics: communication patterns, attitudes about HS, education about HS, response to HS use among hypothetical patients with cancer, knowledge of HS adverse effects, and demographic information. RESULTS: Among eligible oncologists, 392 (42%) responded to the questionnaire. Most were white (75%) men (71%), with a mean age of 48 years (standard deviation, 9.8 years). On average, oncologists discussed use of HS with 41% of their patients; only 26% of discussions were initiated by the oncologist. Two of three oncologists indicated they did not have enough knowledge to answer questions from patients regarding HS, and 59% had not received any education about the topic. Physician factors associated with having initiated discussions with patients about the use of HS included female sex, higher self-reported knowledge, prior education about HS, increased knowledge about HS adverse effects and interactions, and estimating that > 40% of one's patients with cancer use HS. CONCLUSION: Fewer than one half of oncologists are initiating discussions with patients about HS use, and many indicate that lack of knowledge and education is a barrier to such discussions. Improving physician education about HS may facilitate more physician-patient communication about this important topic.

Neo-adjuvant capecitabine chemotherapy in women with newly diagnosed locally advanced breast cancer in a resource-poor setting (Nigeria): efficacy and safety in a phase II feasibility study.

The majority of clinical trials of neo-adjuvant therapy for breast cancer have been conducted in resource-rich countries. We chose Nigeria, a resource-poor country, as the major site for a phase II feasibility open-label multicenter clinical trial designed to evaluate the efficacy, safety, and tolerability of neo-adjuvant capecitabine in locally advanced breast cancer (LABC). Planned treatment consisted of 24 weeks of capecitabine at a dose of 1,000 mg/m(2) twice daily (2,000 mg/m(2) total per day). The primary endpoints were overall, partial, complete clinical response rate (OCR, PCR, CCR) and complete pathologic response (cPR). A total of 16 patients were recruited from August 2007 to April 2010. The study was terminated early as a result of slow accrual. After the first three cycles of therapy, PCR were seen in five of 16 patients (31%; 95% CI 11-59%). Of the remaining 11 patients, eight had no response (NR) or stable disease (SD), and three had progressive disease (PD). Seven patients proceeded with further therapy of which had SD. OCR at the end of eight cycles was 44% (95% CI 20-70%). Clinical response and radiologic response by ultrasonomammography were highly concordant (spearman correlation 0.70). The most common adverse effect was Grade 1 hand-foot syndrome, which was seen in 75% of patients. Despite several limitations, we successfully carried out this phase II feasibility study of neo-adjuvant capecitabine for LABC in Nigeria. Capecitabine monotherapy showed good overall response rates with minimal toxicity and further studies are warranted.

Genetic and functional analysis of CHEK2 (CHK2) variants in multiethnic cohorts.

The CHEK2-1100delC mutation is recurrent in the population and is a moderate risk factor for breast cancer. To identify additional CHEK2 mutations potentially contributing to breast cancer susceptibility, we sequenced 248 cases with early-onset disease; functionally characterized new variants and conducted a population-based case-control analysis to evaluate their contribution to breast cancer risk. We identified 1 additional null mutation and 5 missense variants in the germline of cancer patients. In vitro, the CHEK2-H143Y variant resulted in gross protein destabilization, while others had variable suppression of in vitro kinase activity using BRCA1 as a substrate. The germline CHEK2-1100delC mutation was present among 8/1,646 (0.5%) sporadic, 2/400 (0.5%) early-onset and 3/302 (1%) familial breast cancer cases, but undetectable amongst 2,105 multiethnic controls, including 633 from the US. CHEK2-positive breast cancer families also carried a deleterious BRCA1 mutation. 1100delC appears to be the only recurrent CHEK2 mutation associated with a potentially significant contribution to breast cancer risk in the general population. Another recurrent mutation with attenuated in vitro function, CHEK2-P85L, is not associated with increased breast cancer susceptibility, but exhibits a striking difference in frequency across populations with different ancestral histories. These observations illustrate the importance of genotyping ethnically diverse groups when assessing the impact of low-penetrance susceptibility alleles on population risk. Our findings highlight the notion that clinical testing for rare missense mutations within CHEK2 may have limited value in predicting breast cancer risk, but that testing for the 1100delC variant may be valuable in phenotypically- and geographically-selected populations.