Missed opportunities: Genetic counseling and testing among an ethnically diverse cohort of women with endometrial cancer.

OBJECTIVES: Lynch syndrome (LS) accounts for the majority of inherited endometrial cancers (EC), and the identification of probands presents a unique opportunity to treat and prevent multiple cancers. The diagnosis of EC can provide the indication for women with specific risk factors to undergo genetic testing (GT). We sought to evaluate genetic counseling referrals (GCR) and subsequent GT rates in an ethnically diverse group of high-risk women. METHODS: All women diagnosed with EC between 2011 and 2016 were identified. Risk factors for LS including age, family and personal histories of Lynch-related cancers and loss of tumor mismatch repair (MMR) protein expression were identified from laboratory and medical records. Standard two-sided statistical tests were used. RESULTS: Of 583 women diagnosed with EC, 184 (31.6%) were found to have at least one high-risk characteristic for LS. Among these high-risk women, 58% were given GCR and resulting in only 35% undergoing GT. Ten of the 65 high-risk women who had GT (15.4%) were diagnosed with Lynch syndrome, and all ten met high-risk criteria. Two women of Asian race had tumors exhibiting retained MMR protein expression despite germline testing demonstrating Lynch syndrome. CONCLUSIONS: Many high-risk women do not receive GCR despite a high rate of germline mutations among these women. Improving GCR among high-risk women will lead to more subsequent GT to identify more Lynch syndrome families and prevent additional cancers. Among our ethnically diverse cohort, two women diagnosed with LS had retained MMR protein expression. GCR should be offered to women who possess high-risk characteristics despite normal MMR protein expression.

Comprehensive spectrum of BRCA1 and BRCA2 deleterious mutations in breast cancer in Asian countries.

Approximately 5%-10% of breast cancers are due to genetic predisposition caused by germline mutations; the most commonly tested genes are BRCA1 and BRCA2 mutations. Some mutations are unique to one family and others are recurrent; the spectrum of BRCA1/BRCA2 mutations varies depending on the geographical origins, populations or ethnic groups. In this review, we compiled data from 11 participating Asian countries (Bangladesh, Mainland China, Hong Kong SAR, Indonesia, Japan, Korea, Malaysia, Philippines, Singapore, Thailand and Vietnam), and from ethnic Asians residing in Canada and the USA. We have additionally conducted a literature review to include other Asian countries mainly in Central and Western Asia. We present the current pathogenic mutation spectrum of BRCA1/BRCA2 genes in patients with breast cancer in various Asian populations. Understanding BRCA1/BRCA2 mutations in Asians will help provide better risk assessment and clinical management of breast cancer.

An mHealth model to increase clinic attendance for breast symptoms in rural Bangladesh: can bridging the digital divide help close the cancer divide?

OBJECTIVE: To demonstrate proof of concept for a smart phone-empowered community health worker (CHW) model of care for breast health promotion, clinical breast examination (CBE), and patient navigation in rural Bangladesh. METHODS: This study was a randomized controlled trial; July 1 to October 31, 2012, 30 CHWs conducted door-to-door interviews of women aged 25 and older in Khulna Division. Only women who disclosed a breast symptom were offered CBE. Arm A: smart phone with applications to guide interview, report data, show motivational video, and offer appointment for women with an abnormal CBE. Arm B: smart phone/applications identical to Arm A plus CHW had training in "patient navigation" to address potential barriers to seeking care. Arm C: control arm (no smart phone; same interview recorded on paper). Outcomes are presented as the "adherence" (to advice regarding a clinic appointment) for women with an abnormal CBE. This study was approved by Women's College Hospital Research Ethics Board (Toronto, Ontario, Canada) and district government officials (Khulna, Bangladesh). Funded by Grand Challenges Canada. RESULTS: In 4 months, 22,337 women were interviewed; <1% declined participation, and 556 women had an abnormal CBE. Control group CHWs completed fewer interviews, had inferior data quality, and identified significantly fewer women with abnormal breast exams compared with CHWs in arms A and B. Arm B had the highest adherence. CONCLUSION: CHWs guided by our smart phone applications were more efficient and effective in breast health promotion compared with the control group. CHW "navigators" were most effective in encouraging women with an abnormal breast examination to adhere to advice regarding clinic attendance.

Breast cancer: a neglected disease for the majority of affected women worldwide.

Recent progress with declines in mortality in some high-income countries has obscured the fact that for the majority of women worldwide who are newly diagnosed, breast cancer is a neglected disease in the context of other numerically more frequent health problems. For this growing majority, it is also an orphan disease, in that detailed knowledge about tumor characteristics and relevant host biology necessary to provide even basic care is absent. With the possible exception of nutritional recommendations, current international cancer policy and planning initiatives are irrelevant to breast cancer. The progress that has occurred in high-income countries has come at extraordinary fiscal expense and patient toxicity, which of themselves suggest nonrelevance to women and healthcare practitioners in middle- and low-income countries. The implications of these circumstances appear clear: if the promise of the now 60-year-old Declaration of Human Rights that the fruits of medical science accrue to all mankind is to be realized with respect to breast cancer, a basic and translational global research initiative should be launched.

Cervical and Breast Cancer Screening After CARES: A Community Program for Immigrant and Marginalized Women.

INTRODUCTION: Marginalized populations such as immigrants and refugees are less likely to receive cancer screening. Cancer Awareness: Ready for Education and Screening (CARES), a multifaceted community-based program in Toronto, Canada, aimed to improve breast and cervical screening among marginalized women. This matched cohort study assessed the impact of CARES on cervical and mammography screening among under-screened/never screened (UNS) attendees. METHODS: Provincial administrative data collected from 1998 to 2014 and provided in 2015 were used to match CARES participants who were age eligible for screening to three controls matched for age, geography, and pre-education screening status. Dates of post-education Pap and mammography screening up to June 30, 2014 were determined. Analysis in 2016 compared screening uptake and time to screening for UNS participants and controls. RESULTS: From May 15, 2012 to October 31, 2013, a total of 1,993 women attended 145 educational sessions provided in 20 languages. Thirty-five percent (118/331) and 48% (99/206) of CARES participants who were age eligible for Pap and mammography, respectively, were UNS on the education date. Subsequently, 26% and 36% had Pap and mammography, respectively, versus 9% and 14% of UNS controls. ORs for screening within 8 months of follow-up among UNS CARES participants versus their matched controls were 5.1 (95% CI=2.4, 10.9) for Pap and 4.2 (95%=CI 2.3, 7.8) for mammography. Hazard ratios for Pap and mammography were 3.6 (95% CI=2.1, 6.1) and 3.2 (95% CI=2.0, 5.3), respectively. CONCLUSIONS: CARES' multifaceted intervention was successful in increasing Pap and mammography screening in this multiethnic under-screened population.

Definition and consequences of locally advanced breast cancer.

PURPOSE OF REVIEW: Locally advanced breast cancer (LABC) represents the most advanced stage breast cancer that is still potentially curable with surgery, radiation, and systemic therapy. The purpose of this review is to discuss LABC in the context of modern practice with a focus on its definition and potential consequences. RECENT FINDINGS: There is no one encompassing definition for this disease, but in general cancers of the breast are considered to be locally advanced if they are large and/or have infiltrated into adjacent tissues (the overlying skin or underlying muscles) and/or are found to have extensive locoregional lymph node involvement. It is not surprising, therefore, that LABC can cause significant morbidity and mortality. SUMMARY: Recent advances in our understanding of the biology of breast cancer have made it clear that LABC does not represent a single clinical entity but rather a heterogeneous group of breast tumors that share a common theme of extensive locoregional spread without overt evidence of distant metastatic disease. Despite advances in breast cancer screening and treatment LABC remains a significant global healthcare issue.

Routine TP53 testing for breast cancer under age 30: ready for prime time?

It is well known that early-onset breast cancer may be due to an inherited predisposition. When evaluating women diagnosed with breast cancer under age 30, two important syndromes are typically considered: Hereditary Breast and Ovarian Cancer Syndrome and Li-Fraumeni syndrome. Many women are offered genetic testing for mutations in the BRCA1 and BRCA2 genes; however, few are offered genetic testing for mutations in the TP53 gene. There is a concern that overly restrictive testing of TP53 may fail to recognize families with Li-Fraumeni syndrome. We reviewed the genetic test results and family histories of all women with early-onset breast cancer who had genetic testing of the TP53 gene at the Toronto Hospital for Sick Children. Of the 28 women tested, six (33.3 %) had a mutation in the TP53 gene; a mutation was found in 7.7 % of women who did not meet current criteria for Li-Fraumeni syndrome. By reviewing similar data published between 2000 and 2011, we estimate that 5-8 % of women diagnosed with early-onset breast cancer, and who have a negative family history, may have a mutation in the TP53 gene. Given the potential benefits versus harms of this testing, we discuss the option of simultaneous testing of all three genes (BRCA1, BRCA2, and TP53) for women diagnosed with breast cancer before age 30.

Endometrial cancer and venous thromboembolism in women under age 50 who take tamoxifen for prevention of breast cancer: a systematic review.

BACKGROUND: Breast cancer prevention with tamoxifen in high-risk women is limited due to concerns of endometrial cancer and thromboembolism. We report the risk of endometrial cancer, deep vein thrombosis and pulmonary embolism in women <50 years given tamoxifen for breast cancer prevention. METHODS: We searched the Cochrane Central Register of Controlled Trials and National Library of Medicine for published data from January 1970 to December 2010. We contacted principal investigators of clinical trials, and searched Grey literature and conference proceedings for unpublished data. We reviewed three breast cancer prevention trials comparing tamoxifen (20mg per day) with placebo for five years in high-risk women <50 years. The absolute risk and relative risk (RR) for each outcome were estimated. RESULTS: The RR for endometrial cancer in women <50 years given tamoxifen is 1.19 (95% CI, 0.53-2.65; p=0.6) as compared to the placebo. The RR for deep vein thrombosis with tamoxifen is 2.30 (95% CI, 1.23-4.31; p=0.009) in the active phase of treatment. The risk decreases to 1.00 (95% CI, 0.38-2.67; p=0.9) in the follow-up phase. The RR for pulmonary embolism with tamoxifen is 1.16 (95% CI, 0.55-2.43; p=0.6). INTERPRETATION: The risk of endometrial cancer, deep vein thrombosis and pulmonary embolism is low in women <50 years who take tamoxifen for breast cancer prevention. The risk decreases from the active to follow-up phase of treatment. Education and counseling are the cornerstones of breast cancer chemoprevention.

BRCA1 and BRCA2 families and the risk of skin cancer.

BRCA1 and BRCA2 mutation carriers have elevated risks of breast and ovarian cancers. The risks for cancers at other sites remain unclear. Melanoma has been associated with BRCA2 mutations in some studies, however, few surveys have included non-melanoma skin cancer. We followed 2729 women with a BRCA1 or BRCA2 mutation for an average of 5.0 years. These women were asked to report new cases of cancer diagnosed in themselves or in their family. The risks of skin cancer were compared for probands with BRCA1 and BRCA2 mutations. Of 1779 women with a BRCA1 mutation, 29 developed skin cancer in the follow-up period (1.6%). Of the 950 women with a BRCA2 mutation, 28 developed skin cancer (3.0%) (OR = 1.83 for BRCA2 versus BRCA1; 95% CI 1.08-3.10; P = 0.02). The odds ratio for basal cell carcinoma was higher (OR = 3.8; 95% CI 1.5-9.4; P = 0.002). BRCA2 mutation carriers are at increased risk for skin cancer, compared with BRCA1 carriers, in particular for basal cell carcinoma.

The prevalence of germ-line TP53 mutations in women diagnosed with breast cancer before age 30.

Germ-line mutations in the TP53 gene are rare, but predispose women to a range of cancer types, including early-onset breast cancer. Breast cancers in women from families with the Li-Fraumeni syndrome often occur before age 30. The prevalence of deleterious TP53 mutations in unselected women with early-onset breast cancer is not precisely known. If mutations were found to be sufficiently common, it might be prudent to offer genetic testing to affected women in this age group. We screened the entire TP53 gene in the germ-line DNA from 95 women of various ethnic groups who were diagnosed with breast cancer before age 30, and who had previously been found to be negative for BRCA1 and BRCA2 mutations. No TP53 mutation was found. This study does not support a policy that TP53 testing should be offered routinely to unselected women with early-onset breast cancer in the absence of a family history of cancer.